Submissions for variant NM_000059.4(BRCA2):c.6698C>A (p.Ala2233Asp)

gnomAD frequency: 0.00001  dbSNP: rs41293501

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045020	SCV000073033	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000212250	SCV000210400	uncertain significance	not provided	2018-02-26	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.6698C>A at the cDNA level, p.Ala2233Asp (A2233D) at the protein level, and results in the change of an Alanine to an Aspartic Acid (GCT>GAT). Using alternate nomenclature, this variant would be defined as BRCA2 6926C>A. This variant was observed in at least two individuals with triple negative breast cancer and at least one other from a hereditary diffuse gastric cancer family (Couch 2015, Wong-Brown 2015, Hansford 2015). BRCA2 Ala2233Asp was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Ala2233Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000165875	SCV000216625	likely benign	Hereditary cancer-predisposing syndrome	2021-12-10	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.
Color Diagnostics, LLC DBA Color Health	RCV000165875	SCV000683797	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-01	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with aspartic acid at codon 2233 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 4 individuals affected with breast or ovarian cancer (PMID: 25452441, 25682074, 33471991; Leiden Open Variation Database DB-ID BRCA2_003746) and an individual affected with gastric cancer (PMID: 26182300). A multifactorial analysis also has reported co-occurrence and family history likelihood ratios for pathogenicity of 1.1293 and 0.1569, respectively (PMID: 31131967). This variant has been identified in 2/251286 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.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000165875	SCV000747803	uncertain significance	Hereditary cancer-predisposing syndrome	2018-01-16	criteria provided, single submitter	clinical testing
Counsyl	RCV000113630	SCV000784808	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-12-14	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000165875	SCV003847376	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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323374	SCV004028797	uncertain significance	not specified	2024-08-16	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6698C>A (p.Ala2233Asp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.9e-05 in 1613926 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (1.9e-05 vs 0.00075), allowing no conclusion about variant significance. c.6698C>A has been reported in the literature in multiple individuals with a personal and/or family history of cancer (e.g., Couch_2015, de Juan Jimenez_2011, Wong-Brown_2015, Hansford_2015, Bhai_2021). However, these reports 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: 25452441, 26182300, 25682074, 21147080, 34326862). ClinVar contains an entry for this variant (Variation ID: 52159). Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV000113630	SCV004844298	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with aspartic acid at codon 2233 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 4 individuals affected with breast or ovarian cancer (PMID: 25452441, 25682074, 33471991; Leiden Open Variation Database DB-ID BRCA2_003746) and an individual affected with gastric cancer (PMID: 26182300). A multifactorial analysis also has reported co-occurrence and family history likelihood ratios for pathogenicity of 1.1293 and 0.1569, respectively (PMID: 31131967). This variant has been identified in 2/251286 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.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113630	SCV000146912	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-06-20	no assertion criteria provided	clinical testing