ClinVar Genomic variation as it relates to human health

Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.02375 (European), derived from 1000 genomes (2012-04-30).

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.

p.Thr1915Met in exon 11 of BRCA2: This variant is not expected to have clinical significance because it has been identified in 2.7% (1814/66580) of European chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs4987117) and due to a lack of conservation across species, including >20 mammals which have a methionine (Met) at this position.

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

This alteration is classified as 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.

Converted during submission to Benign.

The BRCA2 p.Thr1915Met variant was identified in 264 of 11658 proband chromosomes (frequency: 0.02) from individuals or families with breast and ovarian cancer (Borg 2010, D'Argenio 2015, Garre 2015, Schenkel 2016, Jalkh 2012, Serrano-Fernandez 2009, Meyer 2012, Cherbal 2012). The variant was also identified in the following databases: dbSNP (ID: rs4987117) as "With other allele", ClinVar (20X benign including review by expert panel ENIGMA, 3x likely benign, 2x uncertain significance), Clinvitae, GeneInsight-COGR (5x benign), Cosmic (3x, confirmed somatic, carcinoma of the large intestine and soft tissue), LOVD 3.0 (108x, predicted neutral), and the BIC Database (16x, not pathogenic). In UMD (41x, neutral biological significance) the variant was identified with co-occurring pathogenic variants: BRCA1 c.5137delG (p.Val1713X) and c.5266dup (p.Gln1756ProfsX74), BRCA2 c.3009_3010delCA (p.His1003GlnfsX5), c.5073dup (p.Trp1692MetfsX3), c.6405_6409delCTTAA (p.Asn2135LysfsX3), and c.7805G>C (p.Arg2602Thr), increasing the likelihood that the p.Thr1915Met variant does not have clinical significance. The variant was also identified by our laboratory in one individual with breast cancer. The variant was not identified in MutDB, ARUP Laboratories, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 4962 of 276776 chromosomes (61 homozygous) at a frequency of 0.02 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 125 of 24016 chromosomes (freq: 0.005), Other in 123 of 6456 chromosomes (freq: 0.02), Latino in 304 of 34410 chromosomes (freq: 0.01), European in 3746 of 126392 chromosomes (freq: 0.03), Ashkenazi Jewish in 161 of 10142 chromosomes (freq: 0.02), East Asian in 2 of 18860 chromosomes (freq: 0.0001), Finnish in 229 of 25748 chromosomes (freq: 0.009), and South Asian in 272 of 30752 chromosomes (freq: 0.009). The p.Thr1915 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 of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.