VCV000126683.112 - ClinVar

NM_024675.4(PALB2):c.2816T>G (p.Leu939Trp)

Germline

Classification

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.

(34)

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.

Conflicting classifications of pathogenicity
Uncertain significance(3); Benign(7); Likely benign(13)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_024675.4(PALB2):c.2816T>G (p.Leu939Trp)

Variation ID: 126683 Accession: VCV000126683.112

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16p12.2 16: 23624027 (GRCh38) [ NCBI UCSC ] 16: 23635348 (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 13, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_024675.4:c.2816T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_078951.2:p.Leu939Trp	missense
NC_000016.10:g.23624027A>C
NC_000016.9:g.23635348A>C
NG_007406.1:g.22331T>G
LRG_308:g.22331T>G
LRG_308t1:c.2816T>G	LRG_308p1:p.Leu939Trp
	Q86YC2:p.Leu939Trp

... more HGVS ... less HGVS

Protein change

L939W

Other names

p.L939W:TTG>TGG

Canonical SPDI

NC_000016.10:23624026:A:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.00080 (C)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00078

1000 Genomes Project 0.00080

The Genome Aggregation Database (gnomAD), exomes 0.00092

Exome Aggregation Consortium (ExAC) 0.00097

Trans-Omics for Precision Medicine (TOPMed) 0.00115

The Genome Aggregation Database (gnomAD) 0.00121

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00154

Links

ClinGen: CA151239 UniProtKB: Q86YC2#VAR_066375 dbSNP: rs45478192 VarSome

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
Gene	OMIM	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.
Familial cancer of breast	Conflicting interpretations of pathogenicity (6)	criteria provided, conflicting classifications	Feb 1, 2024	RCV000114561.39
Hereditary cancer-predisposing syndrome	Conflicting interpretations of pathogenicity (6)	criteria provided, conflicting classifications	Mar 8, 2021	RCV000116092.31
Fanconi anemia complementation group N	Likely benign (1)	criteria provided, single submitter	Apr 27, 2017	RCV000306515.13
not specified	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Aug 15, 2023	RCV000417395.28
not provided	Benign/Likely benign (13)	criteria provided, multiple submitters, no conflicts	Jul 1, 2024	RCV000586156.50
Malignant tumor of breast	Likely benign (1)	no assertion criteria provided	-	RCV001356702.10
Breast and/or ovarian cancer	Likely benign (1)	criteria provided, single submitter	Apr 25, 2023	RCV001170349.12
PALB2-related disorder	Likely benign (1)	no assertion criteria provided	Sep 4, 2019	RCV004528790.2
Hereditary breast ovarian cancer syndrome	Benign (1)	criteria provided, single submitter	Aug 13, 2024	RCV004760375.1

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 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.
Uncertain significance (Jun 01, 2015)	criteria provided, single submitter (Thompson et al. (Breast Cancer Res. 2015)) 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: SCV000268019.1 First in ClinVar: May 11, 2016 Last updated: May 11, 2016	Publications: PubMed (1) PubMed: 26283626 Observation 1: Number of individuals with the variant: 5 Sex: female Geographic origin: Australia Observation 2: Number of individuals with the variant: 8 Sex: female Geographic origin: Australia
Likely benign (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	PALB2-Related Cancer Susceptibility Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000396086.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Publications: PubMed (8) PubMed: 20722467‚ 23935836‚ 24949998‚ 21165770‚ 24141787‚ 21618343‚ 20582465‚ 19635604
Uncertain significance (Jan 16, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. Accession: SCV000747822.1 First in ClinVar: May 03, 2018 Last updated: May 03, 2018
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Fanconi anemia complementation group N Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000396085.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Publications: PubMed (8) PubMed: 19635604‚ 20582465‚ 24141787‚ 21165770‚ 24949998‚ 20722467‚ 21618343‚ 23935836 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Likely benign (Jan 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001440269.1 First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000166658.15 First in ClinVar: Jun 15, 2014 Last updated: Feb 20, 2024
Benign (Aug 20, 2014)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000172799.10 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)
Benign (Apr 11, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000699576.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018	Publications: PubMed (6) PubMed: 23935836‚ 20722467‚ 26564480‚ 23824750‚ 26315354‚ 26534844 Comment: Variant summary: The c.2816T>G variant affects a conserved nucleotide, resulting in amino acid change from Leu to Trp. 4/4 in-silico tools predict damaging outcome for … (more) Variant summary: The c.2816T>G variant affects a conserved nucleotide, resulting in amino acid change from Leu to Trp. 4/4 in-silico tools predict damaging outcome for this variant (SNPs&GO not captured due to low reliability index). However, these predictions have not been validated via in vitro/vivo functional studies yet. This variant is found in 130/130096 control chromosomes at a frequency of 0.0009993, which is about 6 times of the maximal expected frequency of a pathogenic allele (0.0001563), suggesting this variant is likely a benign polymorphism. This variant has been reported in BRCA1/2 negative BrC/OvC patients without strong evidence for causality. In multiple studies, variant was detected in cases with comparable MAF as in tested controls (Thompson_BCR_2015, Ramus_JNCI_2015, etc) suggesting lack of causative effect. Moreover, there are at least two reported pedigrees showed lack of co-segregation of variant with disease (Damiola_Breast Can Res and Treat_2015), further supporting the neural effect of this variant. In addition, two clinical laboratories via ClinVar classified this variant as benign/likely benign, and one other clinical lab and PALB2 database via ClinVar classified this variant as VUS, all without evidence to independently evaluate. Taken together, this variant was classified as Benign variant. (less)
Benign (Dec 28, 2017)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000150001.7 First in ClinVar: May 17, 2014 Last updated: Apr 09, 2018	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)
Likely benign (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001139996.1 First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020
Likely benign (Mar 08, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002530727.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Likely benign (Nov 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV002010966.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023
Likely benign (Aug 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV002551648.4 First in ClinVar: Jul 30, 2022 Last updated: Aug 18, 2023
Likely benign (Apr 25, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) 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: SCV001332923.3 First in ClinVar: May 31, 2020 Last updated: Feb 04, 2024
Likely benign (Aug 25, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001159558.3 First in ClinVar: Feb 10, 2020 Last updated: Feb 20, 2024
Uncertain significance (Oct 27, 2016)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000539986.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Comment: Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more) Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been seen in multiple individuals with breast cancer. It is present in ExAC with a MaxMAF of 0.16%. It is classified in ClinVar with 1 star by multiple submitters: VUS by GeneDx and Peter MacCallum Cancer center, and LB/B by Invitae and Ambry. (less) Method: Genome/Exome Filtration
Likely benign (Jan 13, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000596219.1 First in ClinVar: Aug 27, 2017 Last updated: Aug 27, 2017
Likely benign (Mar 01, 2018)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000786127.2 First in ClinVar: May 26, 2018 Last updated: May 26, 2018	Publications: PubMed (17) PubMed: 25575445‚ 21365267‚ 25186627‚ 24448499‚ 20722467‚ 21618343‚ 27595995‚ 26283626‚ 18302019‚ 23824750‚ 22241545‚ 17200668‚ 21165770‚ 20582465‚ 23935836‚ 24949998‚ 24141787
Likely benign (Apr 06, 2020)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000601772.2 First in ClinVar: Sep 28, 2017 Last updated: Jan 26, 2021	Publications: PubMed (33) PubMed: 26094658‚ 24448499‚ 25186627‚ 24556926‚ 25356972‚ 25479140‚ 27573125‚ 27153395‚ 28440294‚ 20582465‚ 21165770‚ 17200668‚ 18302019‚ 21365267‚ 22241545‚ 21618343‚ 23824750‚ 23935836‚ 20722467‚ 25575445‚ 24141787‚ 24949998‚ 30521987‚ 27397723‚ 26564480‚ 26740942‚ 27328445‚ 27829436‚ 28279176‚ 29052111‚ 29431189‚ 27099641‚ 26283626
Benign (Nov 06, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000685981.2 First in ClinVar: Feb 19, 2018 Last updated: Dec 11, 2022
Benign (Mar 31, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004019226.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Publications: PubMed (1) PubMed: 25085752 Comment: This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants … (more) This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease. (less)
Benign (Aug 13, 2024)	criteria provided, single submitter (ClinGen PALB2 V1.1.0) Method: curation	Hereditary breast ovarian cancer syndrome Affected status: not provided Allele origin: germline	German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne Accession: SCV005373757.1 First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024	Comment: According to the ClinGen ACMG PALB2 v1.1.0 criteria we chose these criteria: BP1 (supporting benign): Missense variants in PALB2 where primarily truncating variants are known … (more) According to the ClinGen ACMG PALB2 v1.1.0 criteria we chose these criteria: BP1 (supporting benign): Missense variants in PALB2 where primarily truncating variants are known to cause disease., BA1 (stand-alone benign): BA1 GnomAD v2+3 non cancer Grpmax FAF NFE >0,1% (less)
Likely benign (Jul 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001245836.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: PALB2: BP1, BS1:Supporting, BS2 Number of individuals with the variant: 14
Likely 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: SCV001551943.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Comment: The PALB2 p.Leu939Trp variant was identified in 19 of 7014 proband chromosomes (frequency: 0.003) from individuals or families with and was present in 2 of … (more) The PALB2 p.Leu939Trp variant was identified in 19 of 7014 proband chromosomes (frequency: 0.003) from individuals or families with and was present in 2 of 1568 control chromosomes (frequency: 0.0013) from healthy individuals (Catucci_2014_24556926, Garcia_2009_18302019, Guenard_2010_20722467, Hofstatter_2011, Rahman_2007_17200668, Tischkowitz_2012_22241545, Wong-Brown_2014_23824750, Hellebrand_2011_21618343). The variant was also identified in the following databases: dbSNP (ID: rs45478192) as â€šÃ„ÃºWith other alleleâ€šÃ„Ã¹, ClinVar (1x as benign by Ambry Genetics, 5x as likely benign by GeneDx, Invitae, Illumina Clinical Services, 5x as uncertain significance by Cancer Genetics Laboratory, Peter MacCallum Cancer Centre Study Description, Laboratory for Molecular Medicine and PALB2 database, Clinvitae (5x), LOVD 3.0 (16x) and Zhejiang Colon Cancer Database (2x). The variant was not identified in the Cosmic, or MutDB databases. The variant was identified in control databases in 271 of 276706 chromosomes at a frequency of 0.001 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 10 of 23938 chromosomes (freq: 0.0004), Other in 5 of 6454 chromosomes (freq: 0.0008), Latino in 22 of 34388 chromosomes (freq: 0.0006), European Non-Finnish in 215 of 126424 chromosomes (freq: 0.002), Ashkenazi Jewish in 18 of 10138 chromosomes (freq: 0.0018), European Finnish in 1 of 25770 chromosomes (freq: 0.00004), while the variant was not observed in the East Asian, and South Asian populations. The variant was also identified by our laboratory in 1 individual with breast cancer with a co-occurring pathogenic BRCA2 variant (c.755-758delACAG, p.Asp252Valfsx24), increasing the likelihood that the p.Leu939Trp variant does not have clinical significance. In one study, researchers indicate that both the leucine amino acids at positions 931 and 939 are conserved in all species, and are located in the WD40-repeat domain responsible for binding to BRCA2 and in a region that mediates the binding with RAD51. Of these two variants, only p.Leu931Arg was not annotated and not found in controls from this study or other previously published studies. The p.Leu939Trp variant is known to be relatively common in both breast cancer patients and in healthy controls thus indicating a more likely benign classification (Catucci_2014). The p.Leu939Trp residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. (less) Number of individuals with the variant: 10
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: SCV001799000.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
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: SCV001743750.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided 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: SCV001905743.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Likely benign (Sep 04, 2019)	no assertion criteria provided Method: clinical testing	PALB2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000807098.3 First in ClinVar: Mar 17, 2018 Last updated: Oct 08, 2024	Comment: This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Likely benign (Nov 19, 2018)	no assertion criteria provided Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	True Health Diagnostics Accession: SCV000886699.1 First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018
Likely benign (May 13, 2019)	no assertion criteria provided Method: curation	not provided Affected status: yes Allele origin: germline	Leiden Open Variation Database Accession: SCV001193292.1 First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020	Publications: PubMed (15) PubMed: 17200668‚ 18302019‚ 20722467‚ 21165770‚ 21365267‚ 21618343‚ 22241545‚ 23824750‚ 23935836‚ 24448499‚ 24556926‚ 24949998‚ 25186627‚ 25356972‚ 25479140 Comment: Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Melissa DeRycke.
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001807303.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001932936.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
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: SCV001956770.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001972797.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
click to load more click to collapse

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

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:

Variant summary: The c.2816T>G variant affects a conserved nucleotide, resulting in amino acid change from Leu to Trp. 4/4 in-silico tools predict damaging outcome for this variant (SNPs&GO not captured due to low reliability index). However, these predictions have not been validated via in vitro/vivo functional studies yet. This variant is found in 130/130096 control chromosomes at a frequency of 0.0009993, which is about 6 times of the maximal expected frequency of a pathogenic allele (0.0001563), suggesting this variant is likely a benign polymorphism. This variant has been reported in BRCA1/2 negative BrC/OvC patients without strong evidence for causality. In multiple studies, variant was detected in cases with comparable MAF as in tested controls (Thompson_BCR_2015, Ramus_JNCI_2015, etc) suggesting lack of causative effect. Moreover, there are at least two reported pedigrees showed lack of co-segregation of variant with disease (Damiola_Breast Can Res and Treat_2015), further supporting the neural effect of this variant. In addition, two clinical laboratories via ClinVar classified this variant as benign/likely benign, and one other clinical lab and PALB2 database via ClinVar classified this variant as VUS, all without evidence to independently evaluate. Taken together, this variant was classified as Benign variant.

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:

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been seen in multiple individuals with breast cancer. It is present in ExAC with a MaxMAF of 0.16%. It is classified in ClinVar with 1 star by multiple submitters: VUS by GeneDx and Peter MacCallum Cancer center, and LB/B by Invitae and Ambry.

Comment:

This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease.

Comment:

According to the ClinGen ACMG PALB2 v1.1.0 criteria we chose these criteria: BP1 (supporting benign): Missense variants in PALB2 where primarily truncating variants are known to cause disease., BA1 (stand-alone benign): BA1 GnomAD v2+3 non cancer Grpmax FAF NFE >0,1%

Comment:

The PALB2 p.Leu939Trp variant was identified in 19 of 7014 proband chromosomes (frequency: 0.003) from individuals or families with and was present in 2 of 1568 control chromosomes (frequency: 0.0013) from healthy individuals (Catucci_2014_24556926, Garcia_2009_18302019, Guenard_2010_20722467, Hofstatter_2011, Rahman_2007_17200668, Tischkowitz_2012_22241545, Wong-Brown_2014_23824750, Hellebrand_2011_21618343). The variant was also identified in the following databases: dbSNP (ID: rs45478192) as â€šÃ„ÃºWith other alleleâ€šÃ„Ã¹, ClinVar (1x as benign by Ambry Genetics, 5x as likely benign by GeneDx, Invitae, Illumina Clinical Services, 5x as uncertain significance by Cancer Genetics Laboratory, Peter MacCallum Cancer Centre Study Description, Laboratory for Molecular Medicine and PALB2 database, Clinvitae (5x), LOVD 3.0 (16x) and Zhejiang Colon Cancer Database (2x). The variant was not identified in the Cosmic, or MutDB databases. The variant was identified in control databases in 271 of 276706 chromosomes at a frequency of 0.001 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 10 of 23938 chromosomes (freq: 0.0004), Other in 5 of 6454 chromosomes (freq: 0.0008), Latino in 22 of 34388 chromosomes (freq: 0.0006), European Non-Finnish in 215 of 126424 chromosomes (freq: 0.002), Ashkenazi Jewish in 18 of 10138 chromosomes (freq: 0.0018), European Finnish in 1 of 25770 chromosomes (freq: 0.00004), while the variant was not observed in the East Asian, and South Asian populations. The variant was also identified by our laboratory in 1 individual with breast cancer with a co-occurring pathogenic BRCA2 variant (c.755-758delACAG, p.Asp252Valfsx24), increasing the likelihood that the p.Leu939Trp variant does not have clinical significance. In one study, researchers indicate that both the leucine amino acids at positions 931 and 939 are conserved in all species, and are located in the WD40-repeat domain responsible for binding to BRCA2 and in a region that mediates the binding with RAD51. Of these two variants, only p.Leu931Arg was not annotated and not found in controls from this study or other previously published studies. The p.Leu939Trp variant is known to be relatively common in both breast cancer patients and in healthy controls thus indicating a more likely benign classification (Catucci_2014). The p.Leu939Trp residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A PALB2 truncating mutation: Implication in cancer prevention and therapy of Hereditary Breast and Ovarian Cancer.	Velázquez C	Breast (Edinburgh, Scotland)	2019	PMID: 30521987
Molecular analysis of PALB2-associated breast cancers.	Lee JEA	The Journal of pathology	2018	PMID: 29431189
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
Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairment.	Chen XS	Scientific reports	2017	PMID: 28440294
PALB2 mutations in BRCA1/2-mutation negative breast and ovarian cancer patients from Poland.	Kluska A	BMC medical genomics	2017	PMID: 28279176
The PALB2 p.Leu939Trp mutation is not associated with breast cancer risk.	Catucci I	Breast cancer research : BCR	2016	PMID: 27829436
PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS.	Southey MC	Journal of medical genetics	2016	PMID: 27595995
Association of PALB2 sequence variants with the risk of early-onset breast cancer in patients from Turkey.	Cecener G	Molecular biology reports	2016	PMID: 27573125
Somatic gene mutation analysis of triple negative breast cancers.	Dillon JL	Breast (Edinburgh, Scotland)	2016	PMID: 27397723
Germline mutations in DNA repair genes may predict neoadjuvant therapy response in triple negative breast patients.	Spugnesi L	Genes, chromosomes & cancer	2016	PMID: 27328445
Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer.	Maxwell KN	American journal of human genetics	2016	PMID: 27153395
PALB2: research reaching to clinical outcomes for women with breast cancer.	Southey MC	Hereditary cancer in clinical practice	2016	PMID: 27099641
Targeted massively parallel sequencing of a panel of putative breast cancer susceptibility genes in a large cohort of multiple-case breast and ovarian cancer families.	Li J	Journal of medical genetics	2016	PMID: 26534844
Identification of point mutations and large intragenic deletions in Fanconi anemia using next-generation sequencing technology.	Nicchia E	Molecular genetics & genomic medicine	2015	PMID: 26740942
Mutation analysis of PALB2 gene in French breast cancer families.	Damiola F	Breast cancer research and treatment	2015	PMID: 26564480
Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer.	Ramus SJ	Journal of the National Cancer Institute	2015	PMID: 26315354
Prevalence of PALB2 mutations in Australian familial breast cancer cases and controls.	Thompson ER	Breast cancer research : BCR	2015	PMID: 26283626
Detection of novel germline mutations for breast cancer in non-BRCA1/2 families.	Aloraifi F	The FEBS journal	2015	PMID: 26094658
Mutation screening of PALB2 in clinically ascertained families from the Breast Cancer Family Registry.	Nguyen-Dumont T	Breast cancer research and treatment	2015	PMID: 25575445
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
Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel.	Tung N	Cancer	2015	PMID: 25186627
Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes.	Pruss D	Breast cancer research and treatment	2014	PMID: 25085752
Assessment of PALB2 as a candidate melanoma susceptibility gene.	Aoude LG	PloS one	2014	PMID: 24949998
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
Breast cancer-associated missense mutants of the PALB2 WD40 domain, which directly binds RAD51C, RAD51 and BRCA2, disrupt DNA repair.	Park JY	Oncogene	2014	PMID: 24141787
Low prevalence of germline PALB2 mutations in Australian triple-negative breast cancer.	Wong-Brown MW	International journal of cancer	2014	PMID: 23824750
Analysis of PALB2 gene in BRCA1/BRCA2 negative Spanish hereditary breast/ovarian cancer families with pancreatic cancer cases.	Blanco A	PloS one	2013	PMID: 23935836
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
PALB2 mutations in familial breast and pancreatic cancer.	Hofstatter EW	Familial cancer	2011	PMID: 21365267
PALB2 mutations in German and Russian patients with bilateral breast cancer.	Bogdanova N	Breast cancer research and treatment	2011	PMID: 21165770
PALB2 analysis in BRCA2-like families.	Adank MA	Breast cancer research and treatment	2011	PMID: 20582465
Evaluation of the contribution of the three breast cancer susceptibility genes CHEK2, STK11, and PALB2 in non-BRCA1/2 French Canadian families with high risk of breast cancer.	Guénard F	Genetic testing and molecular biomarkers	2010	PMID: 20722467
Analysis of the gene coding for the BRCA2-interacting protein PALB2 in familial and sporadic pancreatic cancer.	Tischkowitz MD	Gastroenterology	2009	PMID: 19635604
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
PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene.	Rahman N	Nature genetics	2007	PMID: 17200668
click to load more click to collapse

Text-mined citations for rs45478192 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_024675.4(PALB2):c.2816T>G (p.Leu939Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs45478192 ...