Submissions for variant NM_024675.4(PALB2):c.813T>A (p.Ser271Arg)

gnomAD frequency: 0.00001  dbSNP: rs786203246

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166472	SCV000217269	likely benign	Hereditary cancer-predisposing syndrome	2024-03-27	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	RCV000556676	SCV000633478	uncertain significance	Familial cancer of breast	2024-07-22	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 271 of the PALB2 protein (p.Ser271Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 186821). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl	RCV000556676	SCV000786008	uncertain significance	Familial cancer of breast	2018-01-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166472	SCV000908504	uncertain significance	Hereditary cancer-predisposing syndrome	2019-11-04	criteria provided, single submitter	clinical testing	This missense variant replaces serine with arginine at codon 271 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193465	SCV001362316	uncertain significance	not specified	2024-09-30	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.813T>A (p.Ser271Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251420 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.813T>A has been reported in the literature in one unspecified individual from a cohort of Breast Cancer, Ovarian and pancreatic cancer, without strong evidence for causality (Bono_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 34371384). ClinVar contains an entry for this variant (Variation ID: 186821). Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001555224	SCV001776602	uncertain significance	not provided	2019-11-26	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function
Sema4, Sema4	RCV000166472	SCV002531224	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-10	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000556676	SCV004019139	uncertain significance	Familial cancer of breast	2023-03-30	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000556676	SCV004202074	uncertain significance	Familial cancer of breast	2023-09-21	criteria provided, single submitter	clinical testing