ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.641A>G (p.Asp214Gly) (rs55680408)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031270 SCV000577984 benign Breast-ovarian cancer, familial 1 2017-06-29 reviewed by expert panel curation In our experience this variant always co-occurs in cis with c.594-2A>C. The haplotype of c.[594-2A>C; 641A>G] has been shown to be not pathogenic from comprehensive clinical studies (PMID:27008870). We recommend that if c.641A>G is detected in an individual, presence of c.594-2A>C should be verified. If co-occurrence is confirmed, the combination of the two variants is classified as not pathogenic/benign (see SCV000282252.1). If c.641A>G is detected alone, assume clinical significance uncertain in the absence of further evidence.
Invitae RCV000049077 SCV000077090 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-10-16 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 214 of the BRCA1 protein (p.Asp214Gly). The aspartic acid residue is weakly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs55680408, ExAC 0.003%). This variant was reported in individuals and families affected with breast and/or ovarian cancer (PMID: 16211554, 16683254, 20104584, 26884819). In most of the individuals where this variant was found, another variant (c.594-2A>C) was also identified in the BRCA1 gene. This variant has been reported to be in cis with c.594-2A>C in several cases (PMID: 16211554, 29254167). It is also known as 760A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 37689). An experimental study has shown that this missense change did not impair the homology-directed repair (HDR) activity of BRCA1 protein (PMID: 26689913). 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 RCV000132068 SCV000187131 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-14 criteria provided, single submitter clinical testing The p.D214G variant (also known as c.641A>G), located in coding exon 8 of the BRCA1 gene, results from an A to G substitution at nucleotide position 641. The aspartic acid at codon 214 is replaced by glycine, an amino acid with a few similar properties. This alteration has been detected in conjunction with the BRCA1 alteration c.594-2A>C (IVS9-2A>C) in cis and was predicted to cause a partial exon 10 deletion by an in silico tool; however, a splicing assay showed that a transcript with a partial exon 10 deletion was not detected (Tesoriero AA et al. Hum Mutat. 2005;26:495). This alteration has been detected in an individual diagnosed with breast cancer at age 39 (she also carried the BRCA1 c.594-2A>C and c.4956G>A alterations) whose mother was diagnosed with breast cancer in her late 40s, an individual with bilateral breast cancer, and an individual with an uterine serous carcinoma (Southey MC et al. Br J Cancer. 1999;79:34-9; Borg A et al. Hum Mutat. 2010 Mar;31(3):E1200-40; Pennington KP et al. Cancer. 2013;119:332-8). This alteration has an Align-GVGD score of C0 (least likely to impact function) based on a protein alignment algorithm (Borg A et al. Hum Mutat. 2010 Mar;31(3):E1200-40). In one study, large-scale genetic and clinical resources from the ENIGMA, CIMBA and BCAC consortia were used to assess the pathogenicity of the haplotype (c.594-2A>C linked to c.641A>G) carrying this variant. This resulted in the combined odds for causality of 3.23x10-8 for this haplotype, considering case-control, segregation, and breast tumor pathology information. Their data indicate that c.594-2A>C is always in cis with c.641A>G (de la Hoya M et al Hum Mol Genet. 2016; Mar). Of note, this alteration is also designated as and 760A>G in published literature. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analyses. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000168485 SCV000210080 likely benign not specified 2018-01-02 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587324 SCV000699282 uncertain significance not provided 2016-04-08 criteria provided, single submitter clinical testing Variant summary: c.641A>G is a missense variant located at a non-conserved position in the middle of exon 10, and 3/4 in silico tools predict a benign outcome. The variant of interest is always observed in cis with c.594-2A>C. de la Hoya (2016) showed that in mini-gene assay, the plasmid coding only c.641A>G, mostly produced ex10del but no detectable10p. The finding that c.641A>G causes exon 10 skipping albeit being located outside the splice site, suggests that this variant disturbs the regulation of exon 10 splicing, probably by destroying splicing enhancer elements and/or by creating splicing silencer elements, a hypothesis supported by an in silico analysis based on ESRseq scores. This variant has been found in cis with c.594-2A>C in multiple HBOC patients in the absence of other known pathogenic variants. In addition, it has co-occurred with (unspecified) deleterious mutation in BRCA2 in several families (Myriad data) and 2 different pathogenic variants in BRCA1 in another 2 families. The combined odds for causality for c.[594-2A>C; 641A>G] considering case-control, segregation, and breast tumor pathology information was 3.23xe-8. Authors also conclude that amount of in-frame ex9-10del transcripts arising from the combination of two variants (~20-30%) confer sufficient tumor suppressor activity in vivo to compensate for the lack of full length transcripts (rescue model). In addition, reputable databases/diagnostic centers classify variant as VUS. Based on the latest data c.[594-2A>C; 641A>G] carriers (but not necessarily carriers of c.641A>G in isolation) should not be considered at high-risk of developing BRCA1-associated cancers. Taking all evidence together, the variant was classified to VUS.
Color Health, Inc RCV000132068 SCV000902769 likely benign Hereditary cancer-predisposing syndrome 2016-12-08 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031270 SCV000053875 uncertain significance Breast-ovarian cancer, familial 1 2010-03-15 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031270 SCV000145645 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing

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