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

gnomAD frequency: 0.00003  dbSNP: rs55680408

Total submissions: 13

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	2024-01-21	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 with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 26689913). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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	2022-03-09	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	2023-11-22	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, when testing the protein level effect of this variant (i.e. D214G) in isolation, the variant protein was shown to have proficient HDR activity (Starita_2018). The variant allele was found at a frequency of 5.9e-05 in 1606832control chromosomes (gnomAD database, v4.0 dataset). This frequency is not higher than the estimated maximum expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer Syndrome (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). Eight other submitters, including an expert panel (ENIGMA), have provided clinical-significance assessments for this variant in ClinVar after 2014 partly without evidence for independent evaluation, and classified the variant as VUS (n=4) or likely benign (n=3), while the expert panel classified the variant as VUS in isolation, and benign when occurring as a complex with c.594-2A>C. Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	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	2022-03-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000132068	SCV002537881	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-14	criteria provided, single submitter	curation
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000587324	SCV004563655	uncertain significance	not provided	2023-05-11	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003894829	SCV004712305	benign	BRCA1-related condition	2020-08-11	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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