ClinVar Genomic variation as it relates to human health

IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000000334

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.5% (49/10380) African; ClinVar: 6 B/LB, 2 VUS

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.

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

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.

The BRCA2 p.Gln2384Lys variant was identified in 3 of 4340 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer and was not identified in 280 control chromosomes from healthy individuals (Fackenthal 2005, Gao 2000, Borg 2010). The variant was also identified in dbSNP (ID: rs55977008) “With other allele”, with a minor allele frequency of 0.001 (1000 Genomes Project), and the NHLBI Exome Sequencing Project (Exome Variant Server) in 24 of 4406 African American (frequency 0.005) and 0 of 8600 European American alleles; this variant was identified in the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) 49 of 10380 African, 2 of 11578 latino and 1 of "other" individuals and it was not found in European, European (Non-Finnish), South Asian and East Asian individuals, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The variant was also identified in GeneInsight as unclassified by a clinical laboratory within the Canadian Open Genetics Repository, HGMD, LOVD (predicted neutral, non-pathogenic or of no clinical significance), the BIC database (31X with unknown clinical importance and UMD (6X as a neutral variant and also found co-occurring with silent variant, c.4071A>C (p.Leu1357Leu). The variant was submitted to the ClinVar database by multiple submitters: classified as benign variant by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports) and Ambry Genetics; uncertain significance by BIC and likely benign by Counsyl and by Invitae; classification was not provided by ITMI. The p.Gln2384 residue is not conserved in mammals and lower organisms and 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 p.Gln2384Lys 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. The variant was also identified with high frequency in Algerian and African American breast cancer patients with family history, and BRCA1/2 mutation negative (Cherbal 2012, Nanda 2005). Using a posterior probablility model based on several sources of information for the purpose of VUS classification, the variant was classified as not pathogenic (Lindor 2011). In addition, the variant was found in a patient with uterine serous carcinoma but was not considered a deleterious mutation (Pennington 2013). The variant was identified with a co-occurring BRCA1 pathogenic variant in an individual tested by our lab, increasing the likelihood that this variant is benign. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as benign.