ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.823G>A (p.Gly275Ser) (rs8176153)

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Total submissions: 14
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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) RCV000112797 SCV001161574 benign Breast-ovarian cancer, familial 1 2019-06-18 reviewed by expert panel curation Variant allele has low bioinformatic likelihood to encode a missense alteration affecting protein function (Missense prior probability 0.02; http://priors.hci.utah.edu/PRIORS/), AND low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/), AND minor allele frequency 0.00460 (South Asian), derived from gnomAD v2.1.1 non-cancer (2019-05-13).
Invitae RCV001080861 SCV000077171 benign Hereditary breast and ovarian cancer syndrome 2020-12-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000132245 SCV000187328 likely benign Hereditary cancer-predisposing syndrome 2017-12-19 criteria provided, single submitter clinical testing Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
GeneDx RCV000049158 SCV000210090 likely benign not specified 2018-01-12 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Counsyl RCV000112797 SCV000488322 likely benign Breast-ovarian cancer, familial 1 2016-03-03 criteria provided, single submitter clinical testing
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency RCV000049158 SCV000586872 likely benign not specified 2017-04-18 criteria provided, single submitter clinical testing
Color Health, Inc RCV000132245 SCV000683369 likely benign Hereditary cancer-predisposing syndrome 2016-02-09 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000049158 SCV000699314 likely benign not specified 2019-08-16 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.823G>A (p.Gly275Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00056 in 250402 control chromosomes, predominantly at a frequency of 0.0046 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 4.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.823G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, primarily in individuals of South Asian ethnicity (Vinodkumar_2007, Ahmad_2012, Juwle_2012, Sirisena_2016). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. A large case-control study performed on a multiethnic Asian cohort found there was no association with this variant and increased breast cancer risk (Lai 2017). Co-occurrence with another pathogenic variant has been reported (UMD Database: BRCA2 c.2612C>A, p.Ser871X), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Starita_2015). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000225768 SCV001133653 benign not provided 2019-04-20 criteria provided, single submitter clinical testing
Mendelics RCV000112797 SCV001140619 benign Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000112797 SCV001280986 uncertain significance Breast-ovarian cancer, familial 1 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112797 SCV000145694 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing
Pathway Genomics RCV000112797 SCV000207336 likely benign Breast-ovarian cancer, familial 1 2014-11-06 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000112797 SCV001550873 likely benign Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing The BRCA1 p.Gly275Ser variant was identified in 2 of 596 proband chromosomes (frequency: 0.003) from Pakistani, Thai and Indian individuals or families with unselected, sporadic, or early-onset breast cancer and was not identified in 100 control chromosomes from healthy individuals (Ahmad 2012, Juwle 2012). The variant was also identified in dbSNP (ID: rs8176153) “With other allele”, ClinVar (classified benign by Invitae; as likely benign by Ambry Genetics, GeneDx, Counsyl, and Pathway Genetics; and as uncertain significance by BIC), Genesight-COGR (classified benign/likely benign/uncertain significance by 3 clinical labs), LOVD 3.0 (1x), UMD-LSDB (4x as neutral and co-occurring with a pathogenic variant: BRCA2 c.2612C>A, p.Ser871X), and BIC Database (4x with unknown clinical importance, classification pending). The variant was not identified in Cosmic, MutDB, ARUP Laboratories, or the Zhejiang University Database. The variant was also identified in control databases in 146 (2 homozygous) of 245170 chromosomes at a frequency of 0.0006, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include and South Asian in 146 (2 homozygous) of 30672 chromosomes (freq: 0.005), while not observed in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Gly275 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood Ser impacts the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In a study using DNA methylation with sequence bioinformatics to predict pathogenicity, it was found that the variant was likely not pathogenic (Flower 2015). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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