ClinVar Genomic variation as it relates to human health
NM_024675.4(PALB2):c.2794G>A (p.Val932Met)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(31)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Benign/Likely benign
31
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_024675.4(PALB2):c.2794G>A (p.Val932Met)
Variation ID: 126682 Accession: VCV000126682.103
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 16p12.2 16: 23624049 (GRCh38) [ NCBI UCSC ] 16: 23635370 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 19, 2014 Oct 20, 2024 Aug 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_024675.4:c.2794G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_078951.2:p.Val932Met missense NC_000016.10:g.23624049C>T NC_000016.9:g.23635370C>T NG_007406.1:g.22309G>A LRG_308:g.22309G>A LRG_308t1:c.2794G>A LRG_308p1:p.Val932Met Q86YC2:p.Val932Met - Protein change
- V932M
- Other names
-
p.V932M:GTG>ATG
- Canonical SPDI
- NC_000016.10:23624048:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
0.00100 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 30x 0.00094
1000 Genomes Project 0.00100
Trans-Omics for Precision Medicine (TOPMed) 0.00296
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00431
The Genome Aggregation Database (gnomAD) 0.00449
The Genome Aggregation Database (gnomAD), exomes 0.00517
Exome Aggregation Consortium (ExAC) 0.00597
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| PALB2 | - | - |
GRCh38 GRCh37 |
5913 | 5955 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Benign/Likely benign (4) |
criteria provided, multiple submitters, no conflicts
|
Feb 1, 2024 | RCV000114559.33 | |
| Benign/Likely benign (6) |
criteria provided, multiple submitters, no conflicts
|
Jul 15, 2020 | RCV000116090.26 | |
| Benign/Likely benign (7) |
criteria provided, multiple submitters, no conflicts
|
Aug 15, 2023 | RCV000121760.29 | |
| Benign/Likely benign (8) |
criteria provided, multiple submitters, no conflicts
|
Aug 1, 2024 | RCV000514905.48 | |
| Likely benign (1) |
criteria provided, single submitter
|
Mar 6, 2018 | RCV001118197.12 | |
| Benign (1) |
no assertion criteria provided
|
- | RCV001357367.10 | |
| Benign (1) |
criteria provided, single submitter
|
Apr 6, 2022 | RCV002498482.8 | |
| Benign (1) |
no assertion criteria provided
|
- | RCV001356378.10 | |
| Benign (1) |
criteria provided, single submitter
|
Mar 2, 2022 | RCV003149785.9 | |
| Benign (1) |
criteria provided, single submitter
|
Jul 7, 2023 | RCV003315620.8 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
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Likely benign
(Jun 01, 2015)
|
criteria provided, single submitter
Method: case-control
|
Familial cancer of breast
Cases recruited through familial
(more...)
Affected status: yes, no
Allele origin:
germline
|
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre
Accession: SCV000268018.1
First in ClinVar: May 11, 2016 Last updated: May 11, 2016 |
Observation 1:
Number of individuals with the variant: 23
Sex: female
Geographic origin: Australia
Observation 2:
Number of individuals with the variant: 23
Sex: female
Geographic origin: Australia
|
|
|
Likely benign
(Jun 14, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
PALB2-Related Cancer Susceptibility
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000396087.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
|
|
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Likely benign
(Feb 14, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Accession: SCV000576428.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
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Likely benign
(Feb 17, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000609868.1
First in ClinVar: Nov 05, 2017 Last updated: Nov 05, 2017 |
|
|
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Benign
(Oct 03, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000149999.7
First in ClinVar: May 17, 2014 Last updated: Sep 28, 2017 |
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
|
|
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Benign
(Apr 03, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000860262.1
First in ClinVar: Sep 28, 2017 Last updated: Sep 28, 2017 |
Number of individuals with the variant: 1
Sex: mixed
|
|
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Benign
(Nov 26, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000685979.2
First in ClinVar: Feb 19, 2018 Last updated: Dec 11, 2022 |
|
|
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Benign
(Mar 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV003838082.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
|
|
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Likely benign
(-)
|
criteria provided, single submitter
Method: not provided
|
not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Breakthrough Genomics, Breakthrough Genomics
Accession: SCV005213519.1
First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024 |
|
|
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Benign
(-)
|
criteria provided, single submitter
Method: clinical testing
|
NOT SPECIFIED
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000314374.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
|
|
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Likely benign
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001139997.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
|
|
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Likely benign
(Mar 06, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Fanconi anemia complementation group N
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001276463.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
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Benign
(Jul 15, 2020)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002530723.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
|
|
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Benign
(Apr 06, 2022)
|
criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Fanconi anemia complementation group N Pancreatic cancer, susceptibility to, 3
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002808938.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
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Benign
(Jul 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 5
Affected status: yes
Allele origin:
germline
|
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Accession: SCV004016498.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
|
|
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Likely benign
(Aug 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002551649.4
First in ClinVar: Jul 30, 2022 Last updated: Aug 18, 2023 |
|
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Benign
(Feb 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000153851.16
First in ClinVar: Jun 09, 2014 Last updated: Feb 20, 2024 |
|
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Benign
(Nov 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000604595.6
First in ClinVar: Sep 28, 2017 Last updated: Feb 20, 2024 |
|
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Benign
(Aug 05, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000172810.10
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
|
|
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Likely benign
(Aug 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001150777.27
First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024 |
Comment:
PALB2: BP4, BS2
Number of individuals with the variant: 53
|
|
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Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
Malignant tumor of breast
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001551530.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The PALB2 p.Val932Met variant was identified in 60 of 9444 proband chromosomes (frequency: 0.006) from individuals or families with breast, ovarian and prostate cancer and … (more)
The PALB2 p.Val932Met variant was identified in 60 of 9444 proband chromosomes (frequency: 0.006) from individuals or families with breast, ovarian and prostate cancer and was present in 69 of 12422 control chromosomes (frequency: 0.006) from healthy individuals (Thompson_2015_26283626, Rahman_2007_17200668, Erkko_2007_17287723, Bogdanova_2011_21165770, Wong_2011_21409391, Kuusisto_2011_21356067, Garcia_2009_18302019, Aoude_2014_24949998, Ding_2011_20927582, Prokofyeva_2012_22310028, Hofstatter_2011_21365267, Papi_2010_19763884, Pakkanen_2009_20003494). The variant was also identified in the following databases: dbSNP (ID: rs45624036) as “With other allele”, ClinVar (12x, as benign GeneDx, Invitae, Prevention Genetics, ARUP, Ambry Genetics, Pathway Genetics, PALB2 database, and as likely benign by Cancer Genetics, Illumina, Institute for Biomarker; and ITMI with no indication of clinical significance), Clinvitae (4x, as benign with conflicting pathogenicity), LOVD 3.0 (18x), Zhejiang Colon Cancer Database (4x, as benign with conflicting pathogenicity). The variant was not identified in Cosmic and MutDB, databases. The variant was identified in control databases in 1441 of 276692 chromosomes (4 homozygous) at a frequency of 0.005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 31 of 23944 chromosomes (freq: 0.001295), “Other” in 30 of 6452 chromosomes (freq: 0.00465), Latino in 63 of 34386 chromosomes (freq: 0.001832), European Non-Finnish in 814 of 126400 chromosomes (freq: 0.00644), Ashkenazi Jewish in 43 of 10130 chromosomes (freq: 0.004245), European Finnish in 428 of 25784 chromosomes (freq: 0.0166), and South Asian in 32 of 30744 chromosomes (freq: 0.001041); while the variant was not observed in the East Asian, populations. The p.Val932Met residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. (less)
Number of individuals with the variant: 2
|
|
|
Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
Familial ovarian cancer
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001552823.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The PALB2 p.Val932Met variant was identified in 60 of 9444 proband chromosomes (frequency: 0.006) from individuals or families with breast, ovarian and prostate cancer and … (more)
The PALB2 p.Val932Met variant was identified in 60 of 9444 proband chromosomes (frequency: 0.006) from individuals or families with breast, ovarian and prostate cancer and was present in 69 of 12422 control chromosomes (frequency: 0.006) from healthy individuals (Thompson_2015_26283626, Rahman_2007_17200668, Erkko_2007_17287723, Bogdanova_2011_21165770, Wong_2011_21409391, Kuusisto_2011_21356067, Garcia_2009_18302019, Aoude_2014_24949998, Ding_2011_20927582, Prokofyeva_2012_22310028, Hofstatter_2011_21365267, Papi_2010_19763884, Pakkanen_2009_20003494). The variant was also identified in the following databases: dbSNP (ID: rs45624036) as “With other allele”, ClinVar (12x, as benign GeneDx, Invitae, Prevention Genetics, ARUP, Ambry Genetics, Pathway Genetics, PALB2 database, and as likely benign by Cancer Genetics, Illumina, Institute for Biomarker; and ITMI with no indication of clinical significance), Clinvitae (4x, as benign with conflicting pathogenicity), LOVD 3.0 (18x), Zhejiang Colon Cancer Database (4x, as benign with conflicting pathogenicity). The variant was not identified in Cosmic and MutDB, databases. The variant was identified in control databases in 1441 of 276692 chromosomes (4 homozygous) at a frequency of 0.005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 31 of 23944 chromosomes (freq: 0.001295), “Other” in 30 of 6452 chromosomes (freq: 0.00465), Latino in 63 of 34386 chromosomes (freq: 0.001832), European Non-Finnish in 814 of 126400 chromosomes (freq: 0.00644), Ashkenazi Jewish in 43 of 10130 chromosomes (freq: 0.004245), European Finnish in 428 of 25784 chromosomes (freq: 0.0166), and South Asian in 32 of 30744 chromosomes (freq: 0.001041); while the variant was not observed in the East Asian, populations. The p.Val932Met residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. (less)
Number of individuals with the variant: 2
|
|
|
Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001906424.1 First in ClinVar: Sep 23, 2021 Last updated: Sep 23, 2021 |
|
|
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Likely benign
(Feb 20, 2018)
|
no assertion criteria provided
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
True Health Diagnostics
Accession: SCV000788093.1
First in ClinVar: May 03, 2018 Last updated: May 03, 2018 |
|
|
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Likely benign
(Sep 18, 2019)
|
no assertion criteria provided
Method: curation
|
not provided
Affected status: no
Allele origin:
germline
|
Leiden Open Variation Database
Accession: SCV001193291.1
First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020 |
Comment:
Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Andreas Laner, Carlos Vaccaro, Marc Tischkowitz, Melissa DeRycke.
|
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Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001744010.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
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Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001955682.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
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Benign
(Nov 06, 2014)
|
no assertion criteria provided
Method: clinical testing
|
Breast carcinoma
Affected status: unknown
Allele origin:
germline
|
Pathway Genomics
Accession: SCV000207344.1
First in ClinVar: Feb 06, 2015 Last updated: Feb 06, 2015 |
|
|
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Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001797414.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
|
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Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001808313.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021 |
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not provided
(Sep 19, 2013)
|
no classification provided
Method: reference population
|
AllHighlyPenetrant
Affected status: unknown
Allele origin:
germline
|
ITMI
Accession: SCV000085958.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
Comment:
Please see associated publication for description of ethnicities
|
Observation 1:
Ethnicity/Population group: Whole_cohort
Observation 2:
Ethnicity/Population group: African
Observation 3:
Ethnicity/Population group: African_European
Observation 4:
Ethnicity/Population group: Central_Asian
Observation 5:
Ethnicity/Population group: East_Asian
Observation 6:
Ethnicity/Population group: European
Observation 7:
Ethnicity/Population group: Hispanic
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Citation text
http://evs.gs.washington.edu/EVS/; http://www.1000genomes.org/
Comment on condition
Cases recruited through familial breast cancer clinics in Australia; assessed as having a high probability of familial breast cancer
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Comment:
PALB2: BP4, BS2
Comment:
The PALB2 p.Val932Met variant was identified in 60 of 9444 proband chromosomes (frequency: 0.006) from individuals or families with breast, ovarian and prostate cancer and was present in 69 of 12422 control chromosomes (frequency: 0.006) from healthy individuals (Thompson_2015_26283626, Rahman_2007_17200668, Erkko_2007_17287723, Bogdanova_2011_21165770, Wong_2011_21409391, Kuusisto_2011_21356067, Garcia_2009_18302019, Aoude_2014_24949998, Ding_2011_20927582, Prokofyeva_2012_22310028, Hofstatter_2011_21365267, Papi_2010_19763884, Pakkanen_2009_20003494). The variant was also identified in the following databases: dbSNP (ID: rs45624036) as “With other allele”, ClinVar (12x, as benign GeneDx, Invitae, Prevention Genetics, ARUP, Ambry Genetics, Pathway Genetics, PALB2 database, and as likely benign by Cancer Genetics, Illumina, Institute for Biomarker; and ITMI with no indication of clinical significance), Clinvitae (4x, as benign with conflicting pathogenicity), LOVD 3.0 (18x), Zhejiang Colon Cancer Database (4x, as benign with conflicting pathogenicity). The variant was not identified in Cosmic and MutDB, databases. The variant was identified in control databases in 1441 of 276692 chromosomes (4 homozygous) at a frequency of 0.005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 31 of 23944 chromosomes (freq: 0.001295), “Other” in 30 of 6452 chromosomes (freq: 0.00465), Latino in 63 of 34386 chromosomes (freq: 0.001832), European Non-Finnish in 814 of 126400 chromosomes (freq: 0.00644), Ashkenazi Jewish in 43 of 10130 chromosomes (freq: 0.004245), European Finnish in 428 of 25784 chromosomes (freq: 0.0166), and South Asian in 32 of 30744 chromosomes (freq: 0.001041); while the variant was not observed in the East Asian, populations. The p.Val932Met residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Comment:
The PALB2 p.Val932Met variant was identified in 60 of 9444 proband chromosomes (frequency: 0.006) from individuals or families with breast, ovarian and prostate cancer and was present in 69 of 12422 control chromosomes (frequency: 0.006) from healthy individuals (Thompson_2015_26283626, Rahman_2007_17200668, Erkko_2007_17287723, Bogdanova_2011_21165770, Wong_2011_21409391, Kuusisto_2011_21356067, Garcia_2009_18302019, Aoude_2014_24949998, Ding_2011_20927582, Prokofyeva_2012_22310028, Hofstatter_2011_21365267, Papi_2010_19763884, Pakkanen_2009_20003494). The variant was also identified in the following databases: dbSNP (ID: rs45624036) as “With other allele”, ClinVar (12x, as benign GeneDx, Invitae, Prevention Genetics, ARUP, Ambry Genetics, Pathway Genetics, PALB2 database, and as likely benign by Cancer Genetics, Illumina, Institute for Biomarker; and ITMI with no indication of clinical significance), Clinvitae (4x, as benign with conflicting pathogenicity), LOVD 3.0 (18x), Zhejiang Colon Cancer Database (4x, as benign with conflicting pathogenicity). The variant was not identified in Cosmic and MutDB, databases. The variant was identified in control databases in 1441 of 276692 chromosomes (4 homozygous) at a frequency of 0.005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 31 of 23944 chromosomes (freq: 0.001295), “Other” in 30 of 6452 chromosomes (freq: 0.00465), Latino in 63 of 34386 chromosomes (freq: 0.001832), European Non-Finnish in 814 of 126400 chromosomes (freq: 0.00644), Ashkenazi Jewish in 43 of 10130 chromosomes (freq: 0.004245), European Finnish in 428 of 25784 chromosomes (freq: 0.0166), and South Asian in 32 of 30744 chromosomes (freq: 0.001041); while the variant was not observed in the East Asian, populations. The p.Val932Met residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Comment:
Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Andreas Laner, Carlos Vaccaro, Marc Tischkowitz, Melissa DeRycke.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment on condition
Cases recruited through familial breast cancer clinics in Australia; assessed as having a high probability of familial breast cancer
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Comment:
PALB2: BP4, BS2
Comment:
The PALB2 p.Val932Met variant was identified in 60 of 9444 proband chromosomes (frequency: 0.006) from individuals or families with breast, ovarian and prostate cancer and was present in 69 of 12422 control chromosomes (frequency: 0.006) from healthy individuals (Thompson_2015_26283626, Rahman_2007_17200668, Erkko_2007_17287723, Bogdanova_2011_21165770, Wong_2011_21409391, Kuusisto_2011_21356067, Garcia_2009_18302019, Aoude_2014_24949998, Ding_2011_20927582, Prokofyeva_2012_22310028, Hofstatter_2011_21365267, Papi_2010_19763884, Pakkanen_2009_20003494). The variant was also identified in the following databases: dbSNP (ID: rs45624036) as “With other allele”, ClinVar (12x, as benign GeneDx, Invitae, Prevention Genetics, ARUP, Ambry Genetics, Pathway Genetics, PALB2 database, and as likely benign by Cancer Genetics, Illumina, Institute for Biomarker; and ITMI with no indication of clinical significance), Clinvitae (4x, as benign with conflicting pathogenicity), LOVD 3.0 (18x), Zhejiang Colon Cancer Database (4x, as benign with conflicting pathogenicity). The variant was not identified in Cosmic and MutDB, databases. The variant was identified in control databases in 1441 of 276692 chromosomes (4 homozygous) at a frequency of 0.005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 31 of 23944 chromosomes (freq: 0.001295), “Other” in 30 of 6452 chromosomes (freq: 0.00465), Latino in 63 of 34386 chromosomes (freq: 0.001832), European Non-Finnish in 814 of 126400 chromosomes (freq: 0.00644), Ashkenazi Jewish in 43 of 10130 chromosomes (freq: 0.004245), European Finnish in 428 of 25784 chromosomes (freq: 0.0166), and South Asian in 32 of 30744 chromosomes (freq: 0.001041); while the variant was not observed in the East Asian, populations. The p.Val932Met residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Comment:
The PALB2 p.Val932Met variant was identified in 60 of 9444 proband chromosomes (frequency: 0.006) from individuals or families with breast, ovarian and prostate cancer and was present in 69 of 12422 control chromosomes (frequency: 0.006) from healthy individuals (Thompson_2015_26283626, Rahman_2007_17200668, Erkko_2007_17287723, Bogdanova_2011_21165770, Wong_2011_21409391, Kuusisto_2011_21356067, Garcia_2009_18302019, Aoude_2014_24949998, Ding_2011_20927582, Prokofyeva_2012_22310028, Hofstatter_2011_21365267, Papi_2010_19763884, Pakkanen_2009_20003494). The variant was also identified in the following databases: dbSNP (ID: rs45624036) as “With other allele”, ClinVar (12x, as benign GeneDx, Invitae, Prevention Genetics, ARUP, Ambry Genetics, Pathway Genetics, PALB2 database, and as likely benign by Cancer Genetics, Illumina, Institute for Biomarker; and ITMI with no indication of clinical significance), Clinvitae (4x, as benign with conflicting pathogenicity), LOVD 3.0 (18x), Zhejiang Colon Cancer Database (4x, as benign with conflicting pathogenicity). The variant was not identified in Cosmic and MutDB, databases. The variant was identified in control databases in 1441 of 276692 chromosomes (4 homozygous) at a frequency of 0.005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 31 of 23944 chromosomes (freq: 0.001295), “Other” in 30 of 6452 chromosomes (freq: 0.00465), Latino in 63 of 34386 chromosomes (freq: 0.001832), European Non-Finnish in 814 of 126400 chromosomes (freq: 0.00644), Ashkenazi Jewish in 43 of 10130 chromosomes (freq: 0.004245), European Finnish in 428 of 25784 chromosomes (freq: 0.0166), and South Asian in 32 of 30744 chromosomes (freq: 0.001041); while the variant was not observed in the East Asian, populations. The p.Val932Met residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Comment:
Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Andreas Laner, Carlos Vaccaro, Marc Tischkowitz, Melissa DeRycke.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
| Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer. | Grant RC | Gastroenterology | 2015 | PMID: 25479140 |
| BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study. | Zhen DB | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25356972 |
| Assessment of PALB2 as a candidate melanoma susceptibility gene. | Aoude LG | PloS one | 2014 | PMID: 24949998 |
| Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing. | Bodian DL | PloS one | 2014 | PMID: 24728327 |
| PALB2 sequencing in Italian familial breast cancer cases reveals a high-risk mutation recurrent in the province of Bergamo. | Catucci I | Genetics in medicine : official journal of the American College of Medical Genetics | 2014 | PMID: 24556926 |
| Integrated analysis of germline and somatic variants in ovarian cancer. | Kanchi KL | Nature communications | 2014 | PMID: 24448499 |
| Rare occurrence of PALB2 mutations in ovarian cancer patients from the Volga-Ural region. | Prokofyeva D | Clinical genetics | 2012 | PMID: 22310028 |
| Rare germline mutations in PALB2 and breast cancer risk: a population-based study. | Tischkowitz M | Human mutation | 2012 | PMID: 22241545 |
| BRIP1, PALB2, and RAD51C mutation analysis reveals their relative importance as genetic susceptibility factors for breast cancer. | Wong MW | Breast cancer research and treatment | 2011 | PMID: 21409391 |
| PALB2 mutations in familial breast and pancreatic cancer. | Hofstatter EW | Familial cancer | 2011 | PMID: 21365267 |
| Screening for BRCA1, BRCA2, CHEK2, PALB2, BRIP1, RAD50, and CDH1 mutations in high-risk Finnish BRCA1/2-founder mutation-negative breast and/or ovarian cancer individuals. | Kuusisto KM | Breast cancer research : BCR | 2011 | PMID: 21356067 |
| PALB2 mutations in German and Russian patients with bilateral breast cancer. | Bogdanova N | Breast cancer research and treatment | 2011 | PMID: 21165770 |
| Mutations in BRCA2 and PALB2 in male breast cancer cases from the United States. | Ding YC | Breast cancer research and treatment | 2011 | PMID: 20927582 |
| Analysis of FANCB and FANCN/PALB2 fanconi anemia genes in BRCA1/2-negative Spanish breast cancer families. | García MJ | Breast cancer research and treatment | 2009 | PMID: 18302019 |
| A recurrent mutation in PALB2 in Finnish cancer families. | Erkko H | Nature | 2007 | PMID: 17287723 |
| PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. | Rahman N | Nature genetics | 2007 | PMID: 17200668 |
| http://evs.gs.washington.edu/EVS/; http://www.1000genomes.org/ | - | - | - | - |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PALB2 | - | - | - | - |
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Text-mined citations for rs45624036 ...
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the rs number, so they may include citations for more than one variant
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variant of interest.
Record last updated Nov 10, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.