ClinVar Genomic variation as it relates to human health

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

BS1_Strong,BP4

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: BRCA2 c.517-4C>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.1e-05 in 1590354 control chromosomes, predominantly at a frequency of 0.00063 within the African or African-American subpopulation in the gnomAD database (v4.1 dataset). This frequency is somewhat lower than the estimated maximum expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (0.00075), allowing no clear conclusions about variant significance. However, the variant was also reported from the southern part of Africa with even higher allele frequencies, e.g. 0.014 (3/208 alleles; in the GenomeAsia 100K database) and 0.028 (Oosthuizen_2021), supporting a benign role for the variant. c.517-4C>G has been reported in the literature in individuals affected with breast- and/or ovarian cancer (Pal_2015, Abulkhair_2018, Santonocito_2020), but was also found in controls (Wagner_1999). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 51802). Based on the evidence outlined above, the variant was classified as likely benign.

The BRCA2 c.517-4C>G variant was identified in 2 of 1554 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer and was present in 1 of 190 control chromosomes (frequency: 0.005) from healthy individuals (Abulkhair 2018, Pal 2015, Wagner 1999). The variant was also identified in dbSNP (ID: rs81002804) as "With other allele", ClinVar (classified as benign by Invitae, GeneDx and Sharing Clinical Reports Project (SCRP); as likely benign by Ambry Genetics and two other submitters; and as uncertain significance by three submitters), LOVD 3.0 and the BIC Database (2x with unknown clinical importance). The variant was not identified in UMD-LSDB database. It was identified in control databases in 10 of 277034 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 9 of 24024 chromosomes (freq: 0.0004) and Other in 1 of 6460 chromosomes (freq: 0.0002), while the variant was not observed in the Latino, European, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The c.517-4C>G variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions or position -3 and -5 to -12, which are part of the splicing consensus sequence and sometimes affect splicing. In addition, 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, 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.