ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5207T>C (p.Val1736Ala) (rs45553935)

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Total submissions: 19
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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) RCV000031229 SCV001161713 pathogenic Breast-ovarian cancer, familial 1 2019-06-25 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 Pathogenic based on posterior probability = 0.999.
Invitae RCV000195366 SCV000076870 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-19 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 observed 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 2019-04-30 criteria provided, single submitter clinical testing ​The p.V1736A pathogenic mutation (also known as c.5207T>C), located in coding exon 18 of the BRCA1 gene, results from a T to C substitution at nucleotide position 5207. The valine at codon 1736 is replaced by alanine, an amino acid with similar properties. This mutation is located in a hydrophobic pocket of the BRCA1 protein C-terminal (BRCT) domain and is predicted to affect the stability of residues Pro1749 and Cys1697, both of which are required for BRCT function in DNA repair and tumor suppression. The p.V1736A alteration was reported in trans with a BRCA1 deleterious truncating mutation in an individual with ovarian carcinoma at age 28, short stature, microcephaly, developmental delay, significant toxicity from chemotherapy and both maternal and paternal histories of breast and ovarian cancer. The authors reported the p.V1736A alteration in several other families and it was found to segregate with disease with a combined odds ratio (OR) of 234:1 in favor of p.V1736A being pathogenic (Domchek SM et al. Cancer Discov. 2013 Apr;3(4):399-405). In vitro functional studies show that this mutation results in decreased function of the BRCA1 protein (Carvalho MA et al. Cancer Res. 2007 Feb;67(4):1494-501; Karchin R et al. PLoS Comput. Biol. 2007 Feb;3(2):e26). Furthermore, several evolutionary and structurally based in silico models predict that p.V1736A is deleterious (Mirkovic N et al. Cancer Res. 2004 Jun;64(11):3790-7​; Abkevich VJ. et al. Med. Genet. 2004 Jul;41(7):492-507; Karchin R et al. PLoS Comput. Biol. 2007 Feb;3(2):e26​; Iversen ES et al. Cancer Epidemiol. Biomarkers Prev. 2011 Jun;20(6):1078-88). Of note, this alteration is also designated as 5326T>C in published literature. Based on the available evidence, this alteration is classified as a disease-causing mutation.
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 pathogenic not provided 2019-11-27 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Located in potentially critical domain of the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. Segregation with disease in multiple families.
Counsyl RCV000031229 SCV000677660 pathogenic Breast-ovarian cancer, familial 1 2017-05-17 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131291 SCV000683271 likely pathogenic Hereditary cancer-predisposing syndrome 2020-02-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000195366 SCV000699213 pathogenic Hereditary breast and ovarian cancer syndrome 2020-02-10 criteria provided, single submitter clinical testing BRCA1 c.5207T>C (p.Val1736Ala) results in a non-conservative amino acid change located in the BRCT domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 353058 control chromosomes (gnomAD and publications). c.5207T>C has been reported in the literature in individuals affected with a range of cancers including breast, ovarian, fallopian and/or peritoneal cancers (Carvalho_2007, Domchek_2013, Akbari_2011, Thompson_2016, Shimelis_2017, Judkins_2005, Straub_2018, Arvai_2019). Finch_2016 reports the variant 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 (c.2457delC, legacy name: 2576delC) in a proband with early onset papillary serous ovarian carcinoma, microcephaly, and developmental delay with hypersensitivity to chemotherapy (Domchek_2013). 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. Ten other ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=5)/likely pathogenic(n=5). Some of these submitters provide overlapping evidences utilized in the context of this evaluation. We have observed this variant at an approximate frequency of 0.03% in our tested population and have followed its classification for 6 years (2014-2020) since its initial identification in a patient tested at our laboratory. We had previously classified the variant 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. However, in over five years since its initial evaluation, we have not observed any additional evidence supporting a non-pathogenic outcome and the overall consensus seems to be converging towards pathogenicity. Therefore, based on the evidence outlined above, the variant was re-classified as pathogenic.
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
Mayo Clinic Laboratories, Mayo Clinic RCV000048857 SCV001715192 pathogenic not provided 2020-04-19 criteria provided, single submitter clinical testing PS3, PM2, PM3, PP1_Strong, PP5
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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000031229 SCV000591592 pathogenic Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing The p.Val1736Ala variant was identified in 13 individuals or families with breast or ovarian cancer (Domchek 2013, Carvalho 2007), and was found by Domchek (2013) to co-segregate with cancer in multiple families, with a combined odds ratio in favour of p.Val1736Ala being pathogenic of 234:1. Clinical analysis of tumour samples by Domchek (2013) demonstrated loss of the wild-type allele in some tumours; however, Carvalho (2007) found loss of the variant allele in tumour analysis of a proband. The variant listed in dbSNP (ID: rs45553935), HGMD, LOVD, and the BIC database (18 with unknown clinical importance). The variant was classified as pathogenic by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports). The p.Val1736 residue is conserved across mammals and lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) suggest that the p.Val1736Ala variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. The residue is located in a linker region within the BRCT domain of BRCA1, and the authors of different studies suggest that the p.Val1736Ala variant may affect the stability of the protein and have a long range effect on the binding site (Carvalho 2007, Rowling 2010, Domchek 2013). Rowling (2010) demonstrated a moderately destabilizing effect on the BRCA1 protein using a biophysical approach, Lee (2010) found a significant effect on protein folding stability using a proteolysis assay, and Mirkovic (2004) and Karchin (2007) predicted a deleterious effect on the protein using in silico models. In addition, two studies showed a strong defect on the transcriptional activity of the variant protein (Carvalho 2007, Lee 2010). The results of other assays and analyses in the literature are somewhat conflicting; however these results are limited. One in silico multifactorial-likelihood ratio model classified this as a neutral variant (Easton 2007). One functional study by Rowling (2010) demonstrated that the variant reduced the binding affinity of phosphopeptides; however, another study by Lee (2010) showed intermediate/strong levels of phosphopeptide interaction. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
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
Brotman Baty Institute,University of Washington RCV000031229 SCV001242411 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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