Submissions for variant NM_024675.4(PALB2):c.3056T>C (p.Val1019Ala)

gnomAD frequency: 0.00008  dbSNP: rs376619846

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131550	SCV000186550	likely benign	Hereditary cancer-predisposing syndrome	2020-01-28	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000114589	SCV000255095	likely benign	Familial cancer of breast	2024-01-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000235226	SCV000292803	uncertain significance	not provided	2024-05-29	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate homology-directed repair activity comparable to wildtype (PMID: 31636395); Observed in individuals with breast or ovarian cancer (PMID: 21932393, 26689913, 35264596); This variant is associated with the following publications: (PMID: 21285249, 21932393, 19609323, 26689913, 28873162, 20871615, 24485656, 35264596, 31636395)
Counsyl	RCV000114589	SCV000488746	uncertain significance	Familial cancer of breast	2016-06-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131550	SCV000686005	likely benign	Hereditary cancer-predisposing syndrome	2023-12-13	criteria provided, single submitter	clinical testing
Mendelics	RCV000131550	SCV000839003	uncertain significance	Hereditary cancer-predisposing syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192771	SCV001361099	uncertain significance	not specified	2019-07-26	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.3056T>C (p.Val1019Ala) results in a non-conservative amino acid change located in the WD40 domain that binds to the N-terminus of BRCA2 (IPR031920). Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251450 control chromosomes (gnomAD), exclusively found in the African subpopulation with a frequency of 0.00031 (5/16256). In addition, this variant has been reported in 4/2559 African American women who are older than age 70 and cancer free (in the FLOSSIES database), supporting a benign role for the variant. c.3056T>C has been also reported in the literature in individuals affected with breast or ovarian cancer (Zheng_2012, Lu_2015) and in at least one individual with advanced cancer, type not specified (Mandelker_2017), but without strong evidence for causality. Therefore these reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrences with other pathogenic variant(s) have been reported (PALB2 c.1479delC (p.Thr494LeufsX67) in an internal LCA sample), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Myriad Genetics, Inc.	RCV000114589	SCV004019661	likely benign	Familial cancer of breast	2023-03-31	criteria provided, single submitter	clinical testing	This variant is considered likely 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].
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235226	SCV004222335	uncertain significance	not provided	2023-09-20	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported in affected individuals with breast cancer (PMID: 21932393), as well as unspecified cancers (PMIDs:26689913 (2015) and 28873162 (2017)). Additionally, a functional study suggests that the variant is not damaging to PALB2 protein function (PMIDs: 26689913 (2015) and 31636395 (2020)). The frequency of this variant in the general population, 0.00024 (6/24966 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Leiden Open Variation Database	RCV000114589	SCV001193338	uncertain significance	Familial cancer of breast	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.