Total submissions: 24
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Evidence- |
RCV000031229 | SCV001161713 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 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. |
| Labcorp Genetics |
RCV000195366 | SCV000076870 | pathogenic | Hereditary breast ovarian cancer syndrome | 2024-01-21 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1736 of the BRCA1 protein (p.Val1736Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast, ovarian, and/or peritoneal cancer (PMID: 17308087, 23269703). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 37648). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 17308087, 20378548, 20516115, 23269703). For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV000131291 | SCV000186262 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-10-20 | 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 variant has been detected in trans with a BRCA1 truncating mutation in an individual reported to have clinical features of Fanconi anemia and severe toxicity to chemotherapy (Domchek SM et al. Cancer Discov. 2013 Apr;3(4):399-405). The authors also reported the p.V1736A alteration in several other breast and/or ovarian cancer families, and reported that 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). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). One study found that this nucleotide substitution is non-functional in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature. 2018 Oct;562(7726):217-222). This variant has also been reported to demonstrate impaired transcriptional activity (Carvalho MA et al. Cancer Res. 2007 Feb;67(4):1494-501; Lee MS et al. Cancer Res. 2010 Jun;70(12):4880-90; Fernandes VC et al. J Biol Chem. 2019 Apr;294(15):5980-5992); although in assays of phosphopeptide binding and sensitivity the variant behaved as neutral and intermediate, respectively (Lee MS et al. Cancer Res. 2010 Jun;70(12):4880-90). Studies of drug response reported the variant as having "unclear" findings with regard to cisplatin sensitivity, but reported the alteration as deleterious based on Olaparib response and HRR activity (Bouwman P et al. Cancer Discov. 2013 Oct;3(10):1142-55; Bouwman P et al. Clin Cancer Res. 2020 Sep;26(17):4559-4568). 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. However, because this variant is identified in one or more patients with features of Fanconi anemia, it may be hypomorphic, and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA1 alteration. As risk estimates are unknown at this time, clinical correlation is advised. |
| Gene |
RCV000048857 | SCV000210207 | pathogenic | not provided | 2023-08-23 | criteria provided, single submitter | clinical testing | Observed in 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 2016, Schenkel 2016, Thompson 2016); Published functional studies demonstrate a damaging effect: reduced protein stability, homologous recombination activity, transcriptional activation, and cell survival (Carvalho 2007, Karchin 2007, Lee 2010, Domchek 2013, Findlay 2018, Bouwman 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5236T>C; This variant is associated with the following publications: (PMID: 25782689, 23867111, 26884819, 27836010, 26048987, 15172985, 32719484, 32782288, 32546644, 15235020, 21447777, 17308087, 17924331, 26786923, 26219728, 21702907, 21965345, 20378548, 20516115, 25472942, 25748678, 26913838, 27376475, 28283652, 27760710, 27742776, 23580280, 18992264, 15004537, 16677609, 29133208, 29901183, 29435075, 28781887, 29712865, 30209399, 17305420, 30765603, 32123317, 33087888, 35196514, 23269703, 25348405, 28888541, 34308104, 35665744) |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000048857 | SCV000296377 | pathogenic | not provided | 2019-11-27 | criteria provided, single submitter | clinical testing | This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals affected with hereditary breast and/or ovarian cancer (PMID: 23269703 (2013), 24240112 (2014), 25452441 (2015), 26219728 (2016), 26786923 (2016), 28283652 (2017), 30055521 (2018)). In addition, a female individual with early onset ovarian cancer and clinical evidence of Fanconi anemia was found to carry this variant and another pathogenic BRCA1 variant in trans (i.e., on opposite chromosomes). Pedigree analysis suggests this variant segregates with disease (PMID: 23269703 (2013)). Functional studies have shown that this variant has a deleterious effect on BRCA1 protein function (PMID: 20516115 (2010), 23269703 (2013), 23867111 (2013), 25748678 (2015), 30209399 (2018), 30765603 (2019), 35196514 (2022)). Based on the available information, this variant is classified as pathogenic. |
| Counsyl | RCV000031229 | SCV000677660 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | 2017-05-17 | criteria provided, single submitter | clinical testing | |
| Color Diagnostics, |
RCV000131291 | SCV000683271 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-06-01 | criteria provided, single submitter | clinical testing | This missense variant replaces valine with alanine at codon 1736 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant impacts BRCA1 function in transcription activation and a haploid cell proliferation assay (PMID: 29884841, 30209399) and reduces the stability and function of the BRCA1 protein (PMID: 17308087, 20378548, 20516115, 23269703). This variant has been reported in several individuals and families affected with breast, ovarian, and peritoneal cancer (PMID: 17308087, 22476429, 23269703, 25452441, 26786923, 26219728, 33471991). It has been shown that this variant segregates with disease in two unrelated families (PMID: 23269703). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000195366 | SCV000699213 | pathogenic | Hereditary breast ovarian cancer syndrome | 2021-07-01 | criteria provided, single submitter | clinical testing | Variant summary: 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 (e.g. 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. Twelve other ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. 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. In over five years since its initial evaluation, we have not observed any additional evidence supporting a non-pathogenic outcome. Therefore, based on the evidence outlined above, the variant was classified as pathogenic. |
| Cancer Variant Interpretation Group UK, |
RCV000195366 | SCV000800820 | pathogenic | Hereditary breast 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, |
RCV000048857 | SCV000885080 | likely pathogenic | not provided | 2017-11-08 | criteria provided, single submitter | clinical testing | |
| Mayo Clinic Laboratories, |
RCV000048857 | SCV001715192 | pathogenic | not provided | 2020-04-19 | criteria provided, single submitter | clinical testing | PS3, PM2, PM3, PP1_Strong, PP5 |
| Institute for Biomarker Research, |
RCV000195366 | SCV002819169 | likely pathogenic | Hereditary breast ovarian cancer syndrome | 2022-08-18 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV000031229 | SCV004216871 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | 2024-03-27 | criteria provided, single submitter | clinical testing | |
| Center for Genomic Medicine, |
RCV000048857 | SCV004242801 | pathogenic | not provided | 2024-02-06 | criteria provided, single submitter | clinical testing | |
| All of Us Research Program, |
RCV000031229 | SCV004817576 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | 2023-12-18 | criteria provided, single submitter | clinical testing | This missense variant replaces valine with alanine at codon 1736 in the BRCT1 domain of the BRCA1 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown that this variant causes reduced stability and function of the BRCA1 protein (PMID: 17308087, 20378548, 20516115, 23269703). This variant has been reported to be loss-of-function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in individuals and families affected with breast, ovarian, and peritoneal cancer (PMID: 22476429, 23269703, 25452441, 26219728, 26786923). It has been shown that this variant segregates with disease in several individuals from two unrelated families (PMID: 23269703). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. |
| Laboratory for Molecular Medicine, |
RCV000195366 | SCV004847833 | likely pathogenic | Hereditary breast ovarian cancer syndrome | 2019-10-14 | criteria provided, single submitter | clinical testing | The p.Val1736Ala variant in BRCA1 has been identified in at least 5 individuals with BRCA1-associated cancer and segregated with disease in 4 affected relatives, including 1 obligate carrier (Akbari 2011, Domchek 2013, Finch 2016, Thompson 2016). One of the probands with ovarian cancer, short stature, and developmental delay also carried a loss-of-function variant in BRCA1 in trans (Domchek 2013). This variant was absent from large population studies but has been reported in ClinVar (Variation ID# 37648). Computational prediction tools and conservation analysis suggest that this variant may impact the protein. In addition, the majority of in vitro functional studies support a loss-of-function impact on protein function (Carvalho 2007, Lee 2010, Rowling 2010, Domchek 2013, Gaboriau 2015, Woods 2016, Findlay 2018). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary breast and ovarian cancer. ACMG/AMP Criteria applied: PM2, PS3_Moderate, PP1, PP3, PS4_Supporting. |
| Sharing Clinical Reports Project |
RCV000031229 | SCV000053829 | likely pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | 2013-06-01 | no assertion criteria provided | clinical testing | |
| Breast Cancer Information Core |
RCV000031229 | SCV000145392 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 1 | 2002-05-29 | no assertion criteria provided | clinical testing | |
| Research Molecular Genetics Laboratory, |
RCV000195366 | SCV000587478 | likely pathogenic | Hereditary breast ovarian cancer syndrome | 2015-12-17 | no assertion criteria provided | research | |
| Department of Pathology and Laboratory Medicine, |
RCV000031229 | SCV000591592 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 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, susceptibility to, 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, |
RCV000031229 | SCV001242411 | not provided | Breast-ovarian cancer, familial, susceptibility to, 1 | no assertion provided | in vitro |