ClinVar Miner

Submissions for variant NM_007299.4(BRCA1):c.1895T>C (p.Val632Ala) (rs45553935)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000195366 SCV000076870 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 1736 of the BRCA1 protein (p.Val1736Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals and families affected with breast, ovarian, and peritoneal cancer, with evidence of segregation with disease (PMID: 23269703, 17308087). ClinVar contains an entry for this variant (Variation ID: 37648). Experimental studies have shown that this missense change causes reduced stability and function of the BRCA1 protein (PMID: 23269703, 17308087, 20378548, 20516115). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000131291 SCV000186262 pathogenic Hereditary cancer-predisposing syndrome 2018-04-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Good segregation with disease (lod 1.5-3 = 5-9 meioses),Deficient protein function in appropriate functional assay(s),Other strong data supporting pathogenic classification
GeneDx RCV000048857 SCV000210207 likely pathogenic not provided 2018-07-03 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5207T>C at the cDNA level, p.Val1736Ala (V1736A) at the protein level, and results in the change of a Valine to an Alanine (GTC>GCC). Using alternate nomenclature, this variant is also known as BRCA1 5326T>C. BRCA1 Val1736Ala has been observed in multiple individuals with breast and/or ovarian cancer, with several studied tumors demonstrating loss of the wild-type allele (Akbari 2011, Hondow 2011, Domchek 2013, Finch 2015, Schenkel 2016, Thompson 2016). This variant has also been reported in trans with a pathogenic BRCA1 frameshift variant in an individual with early-onset ovarian cancer and findings suspicious for Fanconi Anemia (Domchek 2013). Functional assays interrogating protein stability, homologous recombination activity, transcriptional activation, and small colony phenotype support pathogenicity, while those investigating cellular response to DNA damage reveal an intermediate effect (Coyne 2004, Carvalho 2007, Lee 2010, Bouwman 2013, Domchek 2013). Although BRCA1 Val1736Ala was predicted by Easton et al. (2007) to be neutral based on a clinical histories, family studies, and co-occurrence with deleterious variants, this predictive model assumes biallelic pathogenic BRCA1 variants to be embryonically lethal. Case reports of patients with BRCA1 homozygous and compound heterozygous pathogenic variants and with a similar presentation (and different variants than the ones mentioned above) provide evidence in support of biallelic BRCA1 pathogenic variants causing a new Fanconi Anemia subtype, FA-S (Sawyer 2015, Freire 2018). BRCA1 Val1736Ala was not observed in large population cohorts (Lek 2016). BRCA1 Val1736Ala is located in the BRCT1 domain and a region known to interact with multiple other proteins (Paul 2014, UniProt). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider BRCA1 Val1736Ala to be a likely pathogenic variant.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000048857 SCV000296377 likely pathogenic not provided 2017-06-07 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000195366 SCV000591592 pathogenic Hereditary breast and ovarian cancer syndrome 2014-10-30 criteria provided, single submitter clinical testing
Counsyl RCV000031229 SCV000677660 pathogenic Breast-ovarian cancer, familial 1 2017-05-17 criteria provided, single submitter clinical testing
Color RCV000131291 SCV000683271 likely pathogenic Hereditary cancer-predisposing syndrome 2018-09-17 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000195366 SCV000699213 likely pathogenic Hereditary breast and ovarian cancer syndrome 2017-06-05 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.5207T>C variant located in the C-Terminal domain involves the alteration of a conserved nucleotide and 4/5 in-silico tools predict a damaging outcome. The variant was not observed in 222980 control chromosomes (including ExAC). This variant was reported in a series of patients reported by Domchek_2013 with a range of cancers to include combinations of breast, ovarian, fallopian and/or peritoneal cancers. Additionally, a recent report by Finch_2016 report its identification in one AJ proband with Melanoma and Breast cancer as well as a family history of breast cancer under the age of 50. It was reported in a biallelic state with another potentially pathogenic BRCA1 variant (2576delC) in a proband with early onset papillary serous ovarian carcinoma, microcephaly, and developmental delay with hypersensitivity to chemotherapy. The transmission of the co-occurring BRCA1 variant in this family is traceable to the paternal lineage, whereas the variant of interest (c.5207T>C) was transmitted maternally. At least one individual, positive for the c.5207T>C variant in the maternal lineage was reportedly unaffected with any cancer at the age of 51. Additionally, Loss of Heterozygosity (LOH) studies have demonstrated a loss of the wild-type allele in at least 2 of the 5 tumors analyzed in these kindreds. The data as presented precludes unequivocal confirmation of cosegregation of the variant among multiple affected and its absence among unaffected individuals in the families reported. A follow-up correspondence with Dr. Susan Domchek, however, assured us that the analysis was performed on a large number of pedigrees that demonstrated strong cosegregation with disease. At least one report, Akbari_2011, classifies this variant as Benign, citing the report by Easton_2007. However, when taking cosegregation data from Domcheck_2013 into account, this variant was predicted to be clearly pathogenic (posterior probability of pathogenicity 0.999, Vallee_2016). Multiple independent experimental functional studies reporting this variant have demonstrated, 1. Reduced localization of BRCA1 fragments containing this variant to double stranded breaks (DSB), 2. Abolished interaction of BRCA1 fragments bearing this variant with RAP80, a BRCT interacting protein, 3. Moderately impaired homology directed DSB repair, 4. Altered binding to the BRCT phosphopeptide binding domain, and 5. Markedly decreased transcriptional activity of the mutant BRCA1 constructs. Although it is not clear whether the results and conclusions drawn from these in-vitro studies are applicable to the mechanism and presentation of disease, the convergence of results obtained from multiple independent functional assays are supportive of a hypomorphic and damaging effect of this variant on the BRCA1 gene product. Therefore, based upon reports of a substantially increased prevalence of this variant among affected individuals compared to controls, and a convergence of multiple in-vitro studies supporting a hypomorphic, yet damaging effect, this variant is classified as Likely Pathogenic, until additional family studies demonstrating unequivocal cosegregation with highly penetrant disease among multiple affected individuals from independent families, and additional data demonstrating LOH are obtained.
Cancer Variant Interpretation Group UK,Institute of Cancer Research, London RCV000195366 SCV000800820 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-13 criteria provided, single submitter clinical testing Data used in classification: The variant was observed in 6 independent UK families undergoing clinical diagnostic testing, the denominator of which dataset of clinical testing was 16,600. Case control comparison against ethnically matched population data (6/16,600 in familial cases against 0/63,369 GNOMAD NFE controls passoc=1.7x10-6 pexact= 8.0x10-5 (PS4_very strong). Seven additional families have been identified in the UK (not included in the previous dataset).There are additional reports of this variant in ClinVar, BIC and BRCA1 LOVD. The variant is absent in the remainder of the GNOMAD populations (75,263 individuals) (PM2). Predicted deleterious on AlignGVGD, SIFT, Polyphen2 HumVar (PP3). Variant found in trans in individual with a phenotype deemed compatible with Fanconi spectrum, including early onset ovarian cancer and sever chemosensitivity (ref PMID:23269703, Domchek 2013) (PM3). Located in BRCT1 domain (PM1_supp). Non-functional using saturation genome editing in haploid BRCA1 cellular model (Findlay et al 2018, BioARchiv). Impaired function on multiple asssays (ref PMID:23269703, Domchek 2013) (PS3_mod). Segregation reported by Domchek et al (5 meioses). Segregation reported by Ambry (5-9 meioses, not clear if independent from Domchek) (PP1_strong). Comment: The observation of this variant in trans with an established pathogenic variant in the Myriad data set strongly influenced the early classification by ENIGMA of this variant as benign (Easton et al 2007), as it had been believed that biallelic germline mutations in BRCA1 were embryonic lethal. However, since 2007, a number of individuals have been reported with biallelic pathogenic mutations in BRCA1.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000048857 SCV000885080 likely pathogenic not provided 2017-11-08 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031229 SCV000053829 likely pathogenic Breast-ovarian cancer, familial 1 2013-06-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031229 SCV000145392 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000195366 SCV000587478 likely pathogenic Hereditary breast and ovarian cancer syndrome 2015-12-17 no assertion criteria provided research
OMIM RCV000585878 SCV000693737 pathogenic FANCONI ANEMIA, COMPLEMENTATION GROUP S 2013-04-01 no assertion criteria provided literature only
OMIM RCV000031229 SCV000693738 pathogenic Breast-ovarian cancer, familial 1 2013-04-01 no assertion criteria provided literature only
True Health Diagnostics RCV000131291 SCV000787909 pathogenic Hereditary cancer-predisposing syndrome 2017-11-15 no assertion criteria provided clinical testing

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