Submissions for variant NM_002878.4(RAD51D):c.208G>A (p.Asp70Asn)

gnomAD frequency: 0.00003  dbSNP: rs142189122

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212955	SCV000149720	uncertain significance	not provided	2024-12-16	criteria provided, single submitter	clinical testing	Observed in individuals with ovarian or colorectal cancer (PMID: 26261251, 28135145, 35263119); Published functional studies are not conclusive: protein interaction levels of XRCC2 and RAD51C similar to wildtype; however, a minigene assay demonstrates increased amount of alternatively spliced transcripts, but the clinical significance is unclear (PMID: 30836272, 34200360); 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: 28135145, 26261251, 34200360, 29641532, 30836272, 35263119, 14704354, 19327148)
Ambry Genetics	RCV000115811	SCV000185442	likely benign	Hereditary cancer-predisposing syndrome	2024-04-11	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000464081	SCV000551346	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 70 of the RAD51D protein (p.Asp70Asn). This variant is present in population databases (rs142189122, gnomAD 0.007%). This missense change has been observed in individual(s) with ovarian cancer and colon cancer (PMID: 26261251, 28135145). ClinVar contains an entry for this variant (Variation ID: 127885). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt RAD51D protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000115811	SCV000686428	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-24	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 70 of the RAD51D protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, protein functional studies have not been reported for this variant. A mini-gene RNA splice study has shown an inconclusive impact of this variant on RNA splicing (PMID: 34200360). This variant has been reported in individuals affected with ovarian cancer (PMID: 26261251) and colorectal cancer (PMID: 28135145). This variant has been identified in 8/251458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Sema4, Sema4	RCV000115811	SCV002534783	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-06	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003114260	SCV003800920	uncertain significance	not specified	2023-01-03	criteria provided, single submitter	clinical testing	Variant summary: RAD51D c.208G>A (p.Asp70Asn) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, at least one functional study showed this variant affected splicing (Bueno-MartAnez_2021). The variant allele was found at a frequency of 3.1e-05 in 257002 control chromosomes (gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.208G>A has been reported in the literature in individuals affected with ovarian cancer or colorectal cancer (Song_2015, Yurelun_2017, Delahunty_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Five ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV000464081	SCV004208089	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2023-10-09	criteria provided, single submitter	clinical testing