Submissions for variant NM_000059.4(BRCA2):c.8902A>G (p.Thr2968Ala)

gnomAD frequency: 0.00001  dbSNP: rs587782021

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130450	SCV000185314	likely benign	Hereditary cancer-predisposing syndrome	2024-10-10	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	RCV000588120	SCV000210487	uncertain significance	not provided	2022-12-16	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 9130A>G; This variant is associated with the following publications: (PMID: 25348012, 26976419, 16683254, 29659569, 12228710, 29884841, 33471991, 32850417, 32377563)
Counsyl	RCV000410479	SCV000487987	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2015-12-10	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588120	SCV000600829	uncertain significance	not provided	2024-07-02	criteria provided, single submitter	clinical testing	The BRCA2 c.8902A>G (p.Thr2968Ala) variant has been reported in individuals with breast cancer (PMID: 26976419 (2016), 33471991 (2021), https://databases.lovd.nl/shared/variants/BRCA2), prostate cancer (PMID: 29659569 (2018)), and ovarian cancer (PMID: 32850417 (2020)). This variant has also been identified in reportedly healthy individuals (PMID: 33471991 (2021), https://databases.lovd.nl/shared/variants/BRCA2). The frequency of this variant in the general population, 0.000011 (3/281158 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 predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000557418	SCV000635698	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 2968 of the BRCA2 protein (p.Thr2968Ala). This variant is present in population databases (rs587782021, gnomAD 0.006%). This missense change has been observed in individual(s) with BRCA2-related conditions (PMID: 26976419, 32850417). ClinVar contains an entry for this variant (Variation ID: 141798). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000160160	SCV000695189	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8902A>G (p.Thr2968Ala) 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 8e-06 in 249760 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8902A>G has been identified in individuals with lung cancer (e.g. Heeke_2020), ovarian cancer (Peixoto_2020) and in settings of multigene panel testing among individuals with breast cancer (e.g., Tung_2015) and prostate cancer (e.g., Paulo_2018). 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. The following publications have been ascertained in the context of this evaluation (PMID: 16683254, 25348012, 26976419, 29659569, 32377563, 32850417, 32066459). ClinVar contains an entry for this variant (Variation ID: 141798). Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000130450	SCV000903030	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-17	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 2968 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 reported in at least one individual each affected with breast, ovarian, or prostate cancer (PMID: 26976419, 29659569, 32850417; Color internal data). This variant also has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 2/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001114). This variant has been identified in 3/281158 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.
Mendelics	RCV000410479	SCV001139237	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000410479	SCV002512308	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2021-11-16	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2 moderate, BP4 supporting
Sema4, Sema4	RCV000130450	SCV002531984	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-27	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV004804154	SCV004846088	uncertain significance	BRCA2-related cancer predisposition	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 2968 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 reported in at least one individual each affected with breast, ovarian, or prostate cancer (PMID: 26976419, 29659569, 32850417; Color internal data). This variant also has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 2/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001114). This variant has been identified in 3/281158 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.