ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.673A>G (p.Thr225Ala)

gnomAD frequency: 0.00001  dbSNP: rs80358897
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000114001 SCV000488347 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2016-03-08 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000758933 SCV000887887 uncertain significance not provided 2018-03-08 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001317442 SCV001508105 uncertain significance Hereditary breast ovarian cancer syndrome 2022-05-14 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 225 of the BRCA2 protein (p.Thr225Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast, ovarian, or endometrial cancer (PMID: 15300854, 22811390, 27383479, 30415210). ClinVar contains an entry for this variant (Variation ID: 52172). 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. 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.
Ambry Genetics RCV002362675 SCV002666955 uncertain significance Hereditary cancer-predisposing syndrome 2023-03-23 criteria provided, single submitter clinical testing The p.T225A variant (also known as c.673A>G), located in coding exon 7 of the BRCA2 gene, results from an A to G substitution at nucleotide position 673. The threonine at codon 225 is replaced by alanine, an amino acid with similar properties. This alteration has been reported in a cohort of 151 uterine serous carcinoma patients (Pennington KP et al. Cancer, 2013 Jan;119:332-8). This alteration has also been reported in 1/88 Korean HBOC patients (Shin S et al. Breast Cancer Res. Treat., 2016 08;158:433-40). This variant was classified as likely benign by a multifactorial analysis incorporating co-occurrence, personal and family history, and tumor characteristic data (Lee JS et al. J. Med. Genet., 2018 12;55:794-802). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Myriad Genetics, Inc. RCV000114001 SCV004043190 likely benign Breast-ovarian cancer, familial, susceptibility to, 2 2023-08-18 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].
All of Us Research Program, National Institutes of Health RCV000114001 SCV004846805 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2023-12-01 criteria provided, single submitter clinical testing This missense variant replaces threonine with alanine at codon 225 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 individuals with a personal or family history of breast and/or ovarian, or endometrial cancer (PMID: 33078592, 27383479, 22811390). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 2/60466 cases and 1/53461 unaffected controls, showing inconclusive association with disease (OR=1.768 (95%CI 0.16 to 19.503); p-value=1; Leiden Open Variation Database DB-ID BRCA2_007740) (PMID: 33471991). 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.
Baylor Genetics RCV004566830 SCV005059016 uncertain significance Familial cancer of breast 2024-03-04 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000114001 SCV000147463 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2002-06-20 no assertion criteria provided clinical testing

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