ClinVar Genomic variation as it relates to human health

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).

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.

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 Syndrome 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 Breast and Ovarian Cancer, primarily in individuals of South Asian ethnicity (example, Vinodkumar_2007, Ahmad_2012, Juwle_2012, Sirisena_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant has been reported in the 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). Multiple clinical diagnostic laboratories and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a predominant consensus as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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.

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.