ClinVar Genomic variation as it relates to human health

Variant summary: BRCA2 c.5554G>A (p.Val1852Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.5e-05 in 295242 control chromosomes (gnomAD and Momozawa_2018). This frequency is lower than the estimated maximum expected for a pathogenic (MPAF) variant in BRCA2 causing Hereditary Breast and Ovarian Cancer Syndrome (0.00075). In addition, the variant was also reported in some East Asian subpopulations with an even higher allele frequency, e.g. in the Japanese, with an allele frequency of 0.000388 (in the jMorp database), although this frequency is also somewhat lower than the MPAF, allowing no clear conclusions about variant significance. c.5554G>A has been reported in the literature in individuals affected with breast- and/or ovarian cancer (e.g. Momozawa_2018, Dorling_2021, Lee_2018, Kim_2020, Kim_2021), and other cancers (Haiman_2013, Dame_2018), as well as in healthy controls (Momozawa_2018, Dorling_2021). Co-occurrences with other pathogenic variants have been reported (BRCA2 c.9076C>T / p.Gln3026X in LOVD, and BRCA1 c.5467+1G>A in two internal LCA samples), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A large scale study utilizing multifactorial probability model for quantitative analysis of BRCA1 and BRCA2 variants predicted this variant to be likely benign (Parsons_2019). Nine other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and multiple laboratories reported the variant with conflicting assessments (VUS, n = 5; likely benign, n = 4). Based on the evidence outlined above, the variant was classified as likely benign.

The BRCA2 c.5554G>A; p.Val1852Ile variant (rs80358777) is reported in the literature in several individuals affected with breast cancer, as well as several healthy controls (Kim 2021, Momozawa 2018). This variant is also reported in ClinVar (Variation ID: 37973). It is observed in the non-Finnish European population with an overall allele frequency of 0.007% (9/127900 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.335). A multifactorial likelihood analysis based on family history, co-segregation and co-occurrence with pathogenic variants suggests that the p.Val1852Ile variant is unlikely to cause disease (Parsons 2019). Due to limited information, the clinical significance of the p.Val1852Ile variant is uncertain at this time. References: Kim JH et al. Analysis of BRCA1/2 variants of unknown significance in the prospective Korean Hereditary Breast Cancer study. Sci Rep. 2021 Apr 19;11(1):8485. PMID: 33875706. Parsons MT et al. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification. Hum Mutat. 2019 Sep;40(9):1557-1578. PMID: 31131967. Momozawa Y et al. Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. Nat Commun. 2018 Oct 4;9(1):4083. PMID: 30287823.

This variant is associated with the following publications: (PMID: 25348012, 23555315, 10923033, 29416916, 29467240, 21520333, 30287823, 31131967)

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).

The BRCA2 c.5554G>A (p.Val1852Ile) missense change has a maximum subpopulation frequency of 0.007% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in an individual with a personal history of breast cancer (PMID: 30287823). To our knowledge, this variant has not been reported in individuals with Fanconi anemia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.

In the published literature, the variant has been reported in individuals with breast cancer (PMID: 33875706 (2021), 33471991 (2021), 30287823 (2018)), pancreatic cancer (PMID: 32980694 (2020)), and prostate cancer (PMID: 23555315 (2013)). The variant has also been identified in unaffected individuals (PMID: 33471991 (2021), 32980694 (2020), 30287823 (2018), 23555315 (2013)). The frequency of this variant in the general population, 0.00007 (9/127900 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.

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.