ClinVar Genomic variation as it relates to human health

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.

RAD51D: BP4, BS1

DNA sequence analysis of the RAD51D gene demonstrated a sequence change, c.932T>A, in exon 10 that results in an amino acid change, p.Ile311Asn. This sequence change has been described in the gnomAD database with a frequency of 0.43% in the East Asian sub-population (dbSNP rs145309168). The p.Ile311Asn change has been reported in individuals with ovarian, breast, and peritoneal cancers (PMIDs: 30111881, 26824983, 22986143). Additionally, two different amino acid changes at the same location, p.Ile311Val and p.Ile311Met, have been reported for predisposition to hereditary breast and ovarian cancer (PMID: 31159747). The p.Ile311Asn change affects a highly conserved amino acid residue located in a domain of the RAD51D protein that is not known to be functional. The p.Ile311Asn substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ile311Asn change remains unknown at this time.

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.

BS1

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22986143, 26824983, 32019284, 18951446, 28961279, 29263802, 29522266, 29338689, 30111881, 31159747, 31514334, 32255556, 32566746, 33785725, 32068069)

The RAD51D p.Ile311Asn variant was identified in 6 of 1426 proband chromosomes (frequency: 0.0042) from individuals or families with breast and ovarian cancer (Lin 2016, Wickramanayake 2012, Wong 2016). The variant was also identified in dbSNP (ID: rs145309168) as “With Uncertain significance, other allele”, ClinVar (as likely benign by Invitae and as uncertain significance by GeneDx, Ambry Genetics and Counsyl), and Clinvitae databases. The variant was not identified in the Cosmic database. The variant was identified in control databases in 122 of 277230 chromosomes at a frequency of 0.00044 in the following populations: European (Non-Finnish) in 26 of 126716 chromosomes (freq. 0.0002), East Asian in 83 (1 homozygous) of 18868 chromosomes (freq. 0.004), European (Finnish) in 2 of 25794 chromosomes (freq. 0.00008) and South Asian in 9 of 30782 chromosomes (freq. 0.0003), and Other in 2 of 6468 chromosomes (freq. 0.0003), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant is located in the ATPase domain of the RAD51D protein (Kim 2011). The p.Ile311Asn residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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 the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

The RAD51D c.932T>A variant is predicted to result in the amino acid substitution p.Ile311Asn. This variant has been reported in over 25 individuals with a personal or family history of breast and/or ovarian cancer (Lin et al. 2016. PubMed ID: 26824983; Table 2 Wong et al. 2016. PubMed ID: 29263802; Supp. Table 1 in Kwong et al. 2020. PubMed ID: 32068069; Hauke et al. 2018. PubMed ID: 29522266; Gervas et al. 2021. PubMed ID: 33785725; Table S5. Tsaousis et al. 2019. PubMed ID: 31159747). This variant has also been reported in individuals with a personal or family history of ovarian cancer (Table 2, Wickramanayake et al. 2012. PubMed ID: 22986143; Konstanta et al. 2018. PubMed ID: 301118810), an individual with gastric cancer (Tedaldi et al. 2019. PubMed ID: 31514334), and an individual with pancreatic ductal adenocarcinoma (Supp. Table 2 Cremin et al. 2020. PubMed ID: 32255556). This variant is reported in 0.43% of alleles in individuals of East Asian descent in gnomAD, including 1 homozygote. The c.932T>A variant has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127896/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.