ClinVar Genomic variation as it relates to human health
NM_024675.4(PALB2):c.1544A>G (p.Lys515Arg)
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.
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.
Uncertain significance(8); Likely benign(5)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_024675.4(PALB2):c.1544A>G (p.Lys515Arg)
Variation ID: 126607 Accession: VCV000126607.39
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p12.2 16: 23635002 (GRCh38) [ NCBI UCSC ] 16: 23646323 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 May 1, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_024675.4:c.1544A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_078951.2:p.Lys515Arg missense NC_000016.10:g.23635002T>C NC_000016.9:g.23646323T>C NG_007406.1:g.11356A>G LRG_308:g.11356A>G LRG_308t1:c.1544A>G LRG_308p1:p.Lys515Arg Q86YC2:p.Lys515Arg - Protein change
- K515R
- Other names
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- Canonical SPDI
- NC_000016.10:23635001:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00005
The Genome Aggregation Database (gnomAD) 0.00009
The Genome Aggregation Database (gnomAD), exomes 0.00009
Trans-Omics for Precision Medicine (TOPMed) 0.00009
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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. |
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PALB2 | - | - |
GRCh38 GRCh37 |
5847 | 5886 |
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. |
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Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jan 6, 2022 | RCV000129175.15 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Feb 1, 2024 | RCV000114479.25 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 13, 2023 | RCV000235723.9 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Nov 3, 2021 | RCV000586359.14 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV001355376.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 2, 2022 | RCV003149776.3 | |
PALB2-related disorder
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Uncertain significance (1) |
criteria provided, single submitter
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Dec 27, 2022 | RCV004528789.1 |
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
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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
(Jul 21, 2015)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000902883.1
First in ClinVar: May 19, 2019 Last updated: May 19, 2019 |
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Uncertain significance
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001140032.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Uncertain significance
(Mar 26, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601732.2
First in ClinVar: Sep 28, 2017 Last updated: Jan 03, 2022 |
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Likely benign
(Jan 06, 2022)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002530622.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Likely benign
(Sep 16, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000292648.13
First in ClinVar: Jul 24, 2016 Last updated: Mar 04, 2023 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27328445, 29052111, 29338072, … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27328445, 29052111, 29338072, 26283626, 22241545, 21618343, 27616075, 25503501, 27930734, 21356067, 28873162, 27997549, 29522266, 31757951, 31159747) (less)
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Uncertain significance
(Mar 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000699539.5
First in ClinVar: Mar 17, 2018 Last updated: May 13, 2023 |
Comment:
Variant summary: PALB2 c.1544A>G (p.Lys515Arg) results in a conservative amino acid change located in the DNA-binding domain (DBD, Nepomuceno_2020) of the encoded protein sequence. Five … (more)
Variant summary: PALB2 c.1544A>G (p.Lys515Arg) results in a conservative amino acid change located in the DNA-binding domain (DBD, Nepomuceno_2020) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.3e-05 in 257362 control chromosomes, predominantly at a frequency of 0.0002 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00016), suggesting the variant may be a benign polymorphism found in the Latino subpopulation. c.1544A>G has been reported in the literature in individuals affected with cancer including Hereditary Breast and Ovarian Cancer and stomach adenocarcinoma but it was also reported in one healthy woman older than 50 years (Hauke_2018, He_2016, Hellebrand_2011, Kraus_2016, Lu_2015, Mandelker_2017, Maxwell_2014, Myszka_2017, Thompson_2015, Tischkowitz_2012, Tsaousis_2019, Akcay_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Moreover, the variant was reported in the FLOSSIES database in two women older than age 70 years who have never had cancer, providing supporting evidence for a benign role. One co-occurrence with a pathogenic variant has been reported internally (APC c.4873delC, p.Gln1625fs*25; internal LCA database). At least one functional study reports this variant has slightly reducing HR activity and no effect on PARPi sensitivity compared to WT (Boonen_2019). Twelve ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=9) and as likely benign (n=5). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. (less)
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Uncertain significance
(Nov 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV003838089.2
First in ClinVar: Mar 11, 2023 Last updated: Feb 04, 2024 |
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Likely benign
(Feb 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000166644.12
First in ClinVar: Jun 15, 2014 Last updated: Feb 14, 2024 |
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Likely benign
(Dec 28, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000183910.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely 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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Uncertain significance
(Jun 01, 2015)
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criteria provided, single submitter
Method: case-control
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Familial cancer of breast
Cases recruited through familial
(more...)
Affected status: yes
Allele origin:
germline
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Cancer Genetics Laboratory, Peter MacCallum Cancer Centre
Accession: SCV000268001.1
First in ClinVar: May 11, 2016 Last updated: May 11, 2016 |
Number of individuals with the variant: 1
Sex: female
Geographic origin: Australia
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Uncertain significance
(Aug 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
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GeneKor MSA
Accession: SCV000822107.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
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Uncertain significance
(Nov 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002010981.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
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Uncertain significance
(Dec 27, 2022)
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criteria provided, single submitter
Method: clinical testing
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PALB2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV000807076.2
First in ClinVar: Sep 13, 2018 Last updated: Nov 20, 2023 |
Comment:
The PALB2 c.1544A>G variant is predicted to result in the amino acid substitution p.Lys515Arg. This variant has been previously reported in patients with familial breast … (more)
The PALB2 c.1544A>G variant is predicted to result in the amino acid substitution p.Lys515Arg. This variant has been previously reported in patients with familial breast cancer (Thompson et al., 2015. PubMed ID: 26283626; Kraus et al., 2017, Table S4, PubMed ID: 27616075). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-23646323-T-C) and in ClinVar it is classified as likely benign and a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/126607/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Uncertain significance
(Dec 04, 2019)
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no assertion criteria provided
Method: curation
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Familial cancer of breast
Affected status: no
Allele origin:
germline
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Leiden Open Variation Database
Accession: SCV001193118.1
First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020 |
Comment:
Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Andreas Laner, Marc Tischkowitz.
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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Familial ovarian cancer
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001550248.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The PALB2 p.Lys515Arg variant was identified in 6 of 10468 proband chromosomes (frequency: 0.00057) from individuals or families with breast or ovarian cancer and was … (more)
The PALB2 p.Lys515Arg variant was identified in 6 of 10468 proband chromosomes (frequency: 0.00057) from individuals or families with breast or ovarian cancer and was not identified in 4896 control chromosomes from healthy individuals (Hellebrand 2011, Kraus 2017, Maxwell 2015, Myszka 2017, Thompson 2015, Tischkowitz 2012). The variant was also identified in dbSNP (ID: rs515726072) as "With Uncertain significance allele", ClinVar (classified as likely benign by Ambry Genetics; as uncertain significance by Invitae, Genedx, PALB2 database and three clinical laboratories), MutDB , and in LOVD 3.0 (1x), databases. The variant was not identified in Cosmic, or Zhejiang University Database. The variant was identified in control databases in 23 of 277248 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6468 chromosomes (freq: 0.00016), Latino in 7 of 34418 chromosomes (freq: 0.0002), European in 15 of 126730 chromosomes (freq: 0.00012), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Lys515 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
Number of individuals with the variant: 1
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
PALB2 Variants: Protein Domains and Cancer Susceptibility. | Nepomuceno TC | Trends in cancer | 2021 | PMID: 33139182 |
Germline pathogenic variant spectrum in 25 cancer susceptibility genes in Turkish breast and colorectal cancer patients and elderly controls. | Akcay IM | International journal of cancer | 2021 | PMID: 32658311 |
Functional Characterization of PALB2 Variants of Uncertain Significance: Toward Cancer Risk and Therapy Response Prediction. | Boonen RACM | Frontiers in molecular biosciences | 2020 | PMID: 33195396 |
Functional analysis of genetic variants in the high-risk breast cancer susceptibility gene PALB2. | Boonen RACM | Nature communications | 2019 | PMID: 31757951 |
Prevalence of genetic susceptibility for breast and ovarian cancer in a non-cancer related study population: secondary germline findings from a Swiss single centre cohort. | Kraemer D | Swiss medical weekly | 2019 | PMID: 31422574 |
Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. | Tsaousis GN | BMC cancer | 2019 | PMID: 31159747 |
Gene panel testing of 5589 BRCA1/2-negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer. | Hauke J | Cancer medicine | 2018 | PMID: 29522266 |
Targeted massively parallel sequencing characterises the mutation spectrum of PALB2 in breast and ovarian cancer cases from Poland and Ukraine. | Myszka A | Familial cancer | 2018 | PMID: 29052111 |
Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing. | Mandelker D | JAMA | 2017 | PMID: 28873162 |
Gene panel sequencing in familial breast/ovarian cancer patients identifies multiple novel mutations also in genes others than BRCA1/2. | Kraus C | International journal of cancer | 2017 | PMID: 27616075 |
Pathogenic Mutations in Cancer-Predisposing Genes: A Survey of 300 Patients with Whole-Genome Sequencing and Lifetime Electronic Health Records. | He KY | PloS one | 2016 | PMID: 27930734 |
Patterns and functional implications of rare germline variants across 12 cancer types. | Lu C | Nature communications | 2015 | PMID: 26689913 |
Prevalence of PALB2 mutations in Australian familial breast cancer cases and controls. | Thompson ER | Breast cancer research : BCR | 2015 | PMID: 26283626 |
Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2-negative patients with early-onset breast cancer. | Maxwell KN | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25503501 |
Rare germline mutations in PALB2 and breast cancer risk: a population-based study. | Tischkowitz M | Human mutation | 2012 | PMID: 22241545 |
Germline mutations in the PALB2 gene are population specific and occur with low frequencies in familial breast cancer. | Hellebrand H | Human mutation | 2011 | PMID: 21618343 |
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Text-mined citations for rs515726072 ...
HelpRecord last updated Jun 23, 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.