Submissions for variant NM_058216.3(RAD51C):c.773G>A (p.Arg258His)

gnomAD frequency: 0.00002  dbSNP: rs267606997

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131703	SCV000186741	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-09-01	criteria provided, single submitter	clinical testing	The p.R258H variant (also known as c.773G>A), located in coding exon 5 of the RAD51C gene, results from a G to A substitution at nucleotide position 773. The arginine at codon 258 is replaced by histidine, an amino acid with highly similar properties. In one Pakistani family, two siblings affected with Fanconi anemia-like disorder were both homozygous for this alteration, while their consanguineous parents were both heterozygous for this alteration and an unaffected sibling was homozygous for the wild type allele (Vaz F et al. Nat. Genet. 2010 May; 42(5):406-9). Multiple functional studies on this alteration have demonstrated impaired protein function, with some evidence suggesting it is a hypomorphic mutant as some residual RAD51C function may be reserved (Vaz F et al. Nat. Genet. 2010 May; 42(5):406-9; Somyajit K et al. Carcinogenesis. 2010 Dec; 31(12):2031-8; Somyajit K et al. J. Biol. Chem. 2012 Jan; 287(5):3366-80;Park JY et al. Oncogene, 2014 Oct;33:4803-12). This alteration has also been reported in cohorts of individuals with increased risk of hereditary breast and/or ovarian cancer (Jønson L et al. Breast Cancer Res. Treat. 2016 Jan; 155(2):215-22; Nguyen-Dumont T et al. Int J Cancer, 2020 10;147:2142-2149; Shao D et al. Cancer Sci, 2020 Feb;111:647-657; Subramanian DN et al. Nat Commun, 2020 04;11:1640). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000007224	SCV000550214	pathogenic	Fanconi anemia complementation group O	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 258 of the RAD51C protein (p.Arg258His). This variant is present in population databases (rs267606997, gnomAD 0.003%). This missense change has been observed in individuals with breast and/or ovarian cancer and features of Fanconi anemia (PMID: 20400963, 25154786, 26740214, 32054657, 32242007). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6822). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RAD51C protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects RAD51C function (PMID: 20400963, 22167183, 26354865). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000506412	SCV000602145	likely pathogenic	not provided	2017-07-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131703	SCV000686387	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-09-14	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 258 in the RAD51B/RAD51D/ XRCC3 interacting domain of the RAD51C protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <=0.5, PMID: 27666373). Functional studies have shown that the mutant protein shows a reduced DNA damage response (PMID: 20400963, 22167183) and reduced ability to bind to other proteins involved in DNA repair (PMID 22167183, 24141787). This variant has been reported in homozygosity in two pediatric siblings and an adult individual showing features of Fanconi anemia (PMID: 20400963, 32054657). This variant has also been observed in an individual affected with familial ovarian cancer (PMID: 32242007) and breast and/or ovarian cancer (PMID: 26740214), as well as in an unaffected individual (PMID 25154786). This variant has been identified in 4/251428 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Mendelics	RCV000007224	SCV001140720	likely pathogenic	Fanconi anemia complementation group O	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194260	SCV001363651	pathogenic	Hereditary breast ovarian cancer syndrome	2019-11-05	criteria provided, single submitter	clinical testing	Variant summary: RAD51C c.773G>A (p.Arg258His) results in a non-conservative amino acid change located in the DNA recombination and repair protein Rad51-like, C-terminal (IPR013632) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251428 control chromosomes (gnomAD). c.773G>A has been reported in the literature as a biallelic mutation in multiple individuals from a family affected with Fanconi-anemia-like disorder (Vaz_2010). The variant has also been reported in at least one patient with breast cancer family history, although this patient also had a co-occurring mutation in BRCA2 that was predicted by the authors to be pathogenic (Ahlborn_2014, Jonson_2016). These data indicate that the variant is likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. Cells expressing the variant protein were shown to have decreased formation of RAD51 foci in response to DNA damage (Vaz_2010), a reduction in binding to other proteins in a complex with BRCA2, PALB2, and RAD51 (Park_2014) and impaired replication fork maintenance (Somyajit_2015). Collectively, these data indicate that the variant results in an impaired ability to repair DNA damage. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV000506412	SCV001871246	likely pathogenic	not provided	2023-12-05	criteria provided, single submitter	clinical testing	Observed in individuals with personal and/or family history of breast and/or ovarian cancer (PMID: 31742824, 32242007, 35039523, 37444530); Published functional studies suggest a damaging effect: failure to protect replication forks, moderately suppressed G2/M accumulation, partial loss of homologous recombination activity and DNA interstrand cross-link repair, reduced RAD51 foci formation, and decreased binding affinity (PMID: 22167183, 25292178, 26354865, 36099300, 37253112, 37488098); Not observed at significant frequency in large population cohorts (gnomAD); 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: 26103414, 20400964, 25833843, 20952512, 21821141, 22167183, 26354865, 20400963, 27037238, 20428093, 26740214, 29278735, 25154786, 29922827, 22451500, 24141787, 28152038, 31589614, 31742824, 32338768, 32090079, 33015624, 32054657, 33804961, 34910513, 30551670, 35039523, 32242007, 37444530, 25292178, 36099300, 37253112, 37488098, 28829762, 27149842, 24998779, 36562461, 35740625, 14704354, 34887416, 36906610)
Myriad Genetics, Inc.	RCV003315500	SCV004020273	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2023-03-10	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 20400963, 32054657]. Functional studies indicate this variant impacts protein function [PMID: 20400963, 36099300, 22167183, 26354865, 24141787].
Baylor Genetics	RCV003315500	SCV004208003	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2024-02-22	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000007224	SCV005086374	pathogenic	Fanconi anemia complementation group O	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with fanconi anaemia, complementation group O (MIM#613390). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (4 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (7 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. Multiple alternative changes at this location have been reported as VUS in ClinVar. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic multiple times in ClinVar. It has also been reported in a consanguineous family with fanconi anaemia (PMID: 20400963). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. The mutation results in loss of RAD51 focus formation in response to DNA damage and in increased cellular sensitivity (PMID: 20400963). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000007224	SCV000027420	pathogenic	Fanconi anemia complementation group O	2010-05-01	no assertion criteria provided	literature only
Leiden Open Variation Database	RCV000007224	SCV001365274	pathogenic	Fanconi anemia complementation group O	2010-08-11	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.