ClinVar Miner

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

gnomAD frequency: 0.00003  dbSNP: rs55680408
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Total submissions: 11
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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, susceptibility to, 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 ovarian cancer syndrome 2021-12-16 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 214 of the BRCA1 protein (p.Asp214Gly). This variant is present in population databases (rs55680408, gnomAD 0.007%). This variant has been observed in trans (on the opposite chromosome) from at least two different pathogenic variants in BRCA1, in individuals affected with breast cancer (PMID: 25639900, Invitae). Considering that biallelic pathogenic variants are expected to be lethal, this evidence indicates that this variant is not a primary cause of disease. This variant is generally observed on the same chromosome as a second BRCA1 variant, c.594-2A>C. Comprehensive clinical validation studies have shown that this BRCA1 haplotype c.[594-2A>C; 641A>G] is not disease causing (PMID: 27008870, 25639900). ClinVar contains an entry for this variant (Variation ID: 37689). 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 BRCA1 protein function. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (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 RCV000587324 SCV000210080 likely benign not provided 2021-04-19 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 26727311, 27495310, 29168416, 28534081, 20104584, 16683254, 20127978, 22811390, 16211554, 26884819, 27008870, 27313609, 26913838, 27515922, 17972171, 26689913, 25348012, 29254167, 28588830, 28695303)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001824579 SCV000699282 likely benign not specified 2022-01-20 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.641A>G (p.Asp214Gly) 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. However, in vitro functional studies have shown that the variant in isolation leads to an out-of-frame exon 10 skipping (likely resulting in NMD). As c.641A>G is located outside of splice sites, this variant probably disturbs the regulation of exon 10 splicing by destroying splicing enhancer and/or creating splicing silencer elements, a hypothesis supported by an in silico analysis (de la Hoya 2016). On the other hand, the variant very frequently, if not always, is found in complex with c.594-2A>C (located in intron 9), and the two together were shown also to cause an out-of-frame exon 10 skipping. Notably, though the double mutant allele c.[594-2A>C; 641A>G] did not produce detectable levels of full-length transcripts, it produced normal levels of the delta 9,10 transcripts (which is a naturally occurring alternative transcript, with an in-frame deletion of exon 9 and 10), predicted to encode a BRCA1 protein with sufficient tumor suppression function to compensate for the lack of full length transcripts (de la Hoya 2016). Additionally, the variant alone was shown to have proficient HDR activity (Starita_2018). The variant allele was found at a frequency of 5.1e-05 in 295836 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (5.1e-05 vs 0.001), allowing no conclusion about variant significance. This variant has been found in many HBOC patients, in most cases as a complex allele in cis with c.594-2A>C, however, the complex variant has also been found to co-occur with other pathogenic BRCA mutations (see e.g. Wong-Brown 2016) and other cancer-gene mutations (Lattimore_2021). In addition, a multifactorial analysis considering large scale case-control, segregation and breast cancer pathology information for the complex allele c.[594-2A>C; 641A>G] predicted the complex variant to be not pathogenic (de la Hoya 2016). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Four submitters classified the variant as likely benign, three as VUS and one expert panel classified the variant as benign. Based on the evidence outlined above, the variant was classified as likely benign.
Color Health, Inc RCV000132068 SCV000902769 likely benign Hereditary cancer-predisposing syndrome 2016-12-08 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001798036 SCV002043461 uncertain significance Breast and/or ovarian cancer 2020-10-14 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587324 SCV002046875 likely benign not provided 2020-10-13 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000132068 SCV002537881 uncertain significance Hereditary cancer-predisposing syndrome 2022-01-14 criteria provided, single submitter curation
Sharing Clinical Reports Project (SCRP) RCV000031270 SCV000053875 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2010-03-15 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031270 SCV000145645 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2002-05-29 no assertion criteria provided clinical testing

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