Submissions for variant NM_000059.4(BRCA2):c.428C>G (p.Pro143Arg)

gnomAD frequency: 0.00001  dbSNP: rs587782795

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132345	SCV000187434	likely benign	Hereditary cancer-predisposing syndrome	2022-09-13	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.
GeneDx	RCV000590737	SCV000210238	uncertain significance	not provided	2019-11-20	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 656C>G
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590737	SCV000296633	uncertain significance	not provided	2024-03-06	criteria provided, single submitter	clinical testing	The BRCA2 c.428C>G (p.Pro143Arg) variant has reported in the published literature in a reportedly healthy individual (PMID: 30630528 (2019)). The frequency of this variant in the general population, 0.00028 (10/35318 chromosomes, http://gnomad.broadinstitute.org), is uninformative in 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 conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000132345	SCV000688865	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-08	criteria provided, single submitter	clinical testing	This missense variant replaces proline with arginine at codon 143 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in individuals affected with BRCA2-associated cancers and relevant family history (Color internal data). This variant has been identified in 10/282048 chromosomes 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	RCV001175343	SCV000694764	uncertain significance	not specified	2021-08-09	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.428C>G (p.Pro143Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 250698 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.428C>G in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637494	SCV000758955	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-02-02	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 143 of the BRCA2 protein (p.Pro143Arg). This variant is present in population databases (rs587782795, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 142885). 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 disruptive. 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.
Sema4, Sema4	RCV000132345	SCV002533865	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-17	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV003315919	SCV004018678	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-13	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV004567154	SCV005059065	uncertain significance	Familial cancer of breast	2024-02-10	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004804663	SCV005424239	uncertain significance	BRCA2-related cancer predisposition	2024-05-09	criteria provided, single submitter	clinical testing	This missense variant replaces proline with arginine at codon 143 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in individuals affected with BRCA2-associated cancers and relevant family history (Color internal data). This variant has been identified in 10/282048 chromosomes 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.
Fulgent Genetics, Fulgent Genetics	RCV005008043	SCV005634391	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3; Familial prostate cancer	2024-06-07	criteria provided, single submitter	clinical testing