Submissions for variant NM_000059.4(BRCA2):c.1478C>T (p.Pro493Leu)

dbSNP: rs786202916

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165981	SCV000216739	likely benign	Hereditary cancer-predisposing syndrome	2018-12-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Counsyl	RCV000239257	SCV000488285	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-02-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000587856	SCV000566694	uncertain significance	not provided	2019-11-19	criteria provided, single submitter	clinical testing	Observed in individuals with breast cancer (Yang 2017); 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; Also known as 1706C>T; This variant is associated with the following publications: (PMID: 28664506, 31131967)
Invitae	RCV000534241	SCV000635162	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000486205	SCV000694542	uncertain significance	not specified	2023-03-31	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1478C>T (p.Pro493Leu) 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 allele was found at a frequency of 4.1e-06 in 243540 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1478C>T has been reported in the literature in individuals affected with Breast Cancer (example, Yang_2017) and ovarian cancer (Delhaunty_2022) without strong evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. 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 and classified the variant as VUS (n=3) and likely benign (n=3). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587856	SCV000888981	uncertain significance	not provided	2023-05-09	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported in individuals with breast cancer (PMID: 28664506 (2017), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRCA2)), as well as unaffected individuals (PMID: 26283626 (2015), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRCA2)). It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000165981	SCV000903160	likely benign	Hereditary cancer-predisposing syndrome	2016-10-11	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000165981	SCV003851419	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353888	SCV000591747	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Pro493Leu variant has not been reported in the literature. This residue is not conserved in mammals and the variant amino acid Leucine (Leu) is present in the cat and dog, increasing the likelihood that an alteration to this residue may not have functional significance. Computational analyses (PolyPhen, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. It is identified in one individual by our laboratory who had a second pathogenic variant, increasing the likelihood this variant doesn not have clinical significance. 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 predicted benign.