ClinVar Genomic variation as it relates to human health

The RAD51D c.413A>G; p.Asn138Ser variant (rs201676898) is reported in the literature in individuals with hereditary cancer syndromes (Boni 2022, Sanchez-Bermudez 2018, Shindo 2017, Tsaousis 2019), and is reported in ClinVar (Variation ID: 127889). This variant is observed in the general population with an overall allele frequency of 0.01% (32/282836 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is neutral (REVEL: 0.061). Based on available information, the clinical significance of this variant is uncertain at this time. References: Boni J et al. A decade of RAD51C and RAD51D germline variants in cancer. Hum Mutat. 2022 Mar;43(3):285-298. PMID: 34923718. Sanchez-Bermudez AI et al. Mutational analysis of RAD51C and RAD51D genes in hereditary breast and ovarian cancer families from Murcia (southeastern Spain). Eur J Med Genet. 2018 Jun;61(6):355-361. PMID: 29409816. Shindo K et al. Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma. J Clin Oncol. 2017 Oct 20;35(30):3382-3390. PMID: 28767289. Tsaousis GN et al. Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. BMC Cancer. 2019 Jun 3;19(1):535. PMID: 31159747.

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.

Observed in individuals with a personal or family history including breast, ovarian, prostate, and other cancers, but also seen in unaffected controls (PMID: 25111073, 25186627, 27443514, 28767289, 29409816, 31159747, 34923718, 33471991, 35893033); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25186627, 28767289, 25111073, 27443514, 29409816, 31159747, 34923718, 35893033, 33471991, 21111057, 14704354, 19327148)

Variant summary: RAD51D c.413A>G (p.Asn138Ser) results in a conservative amino acid change located in the AAA+ ATPase domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 251474 control chromosomes, predominantly at a frequency of 0.00055 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD51D causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.413A>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome, prostate cancer, endometrial carcinoma, or pancreatic cancer (e.g. Johnson_2014, Tung_2015, Ring_2016, Shindo_2017, Sanchez-Bermudez_2018, Tsaousis_2019). 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign n=2, VUS n=3). Based on the evidence outlined above, the variant was classified as likely benign.

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.

The frequency of this variant in the general population, 0.00054 (19/35438 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with hereditary breast and/or ovarian cancer (HBOC) (PMIDs: 31159747 (2019), 29409816 (2018), 25186627 (2015)), prostate cancer (PMIDs: 28767289 (2017), 25111073 (2014)), and endometrial cancer (PMID: 27443514 (2016)). It has been reported in individuals with breast cancer as well as in unaffected controls in a breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/RAD51D)). 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.