Submissions for variant NM_002878.4(RAD51D):c.349T>A (p.Cys117Ser)

dbSNP: rs786201358

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163461	SCV000214012	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-09	criteria provided, single submitter	clinical testing	The p.C117S variant (also known as c.349T>A), located in coding exon 5 of the RAD51D gene, results from a T to A substitution at nucleotide position 349. The cysteine at codon 117 is replaced by serine, an amino acid with dissimilar properties. In one study, this alteration was detected in 1/3429 patients with invasive epithelial ovarian cancer and 0/2772 controls (Song H et al. J. Clin. Oncol. 2015 Sep;33:2901-7). This alteration has also been detected in 1/1781 individuals with a breast cancer diagnosis (Tung N. Cancer. 2015 Jan;121(1):25-33). In addition, this alteration was reported in 4/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl	RCV000410914	SCV000489115	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2016-08-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000410914	SCV000551381	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2024-11-20	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 117 of the RAD51D protein (p.Cys117Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer and ovarian cancer (PMID: 25186627, 26261251). ClinVar contains an entry for this variant (Variation ID: 184247). 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%. Studies have shown that this missense change is associated with inconclusive levels of altered splicing (PMID: 28905878; internal data). 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.
GeneDx	RCV000478670	SCV000565464	uncertain significance	not provided	2024-07-12	criteria provided, single submitter	clinical testing	Observed in individuals with breast or ovarian cancer, but also seen in unaffected controls (PMID: 26261251, 25186627, 33471991); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26261251, 25186627, 21111057, 14704354, 19327148, 33471991)
Color Diagnostics, LLC DBA Color Health	RCV000163461	SCV000686447	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-06	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with serine at codon 117 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, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer or ovarian cancer (PMID: 25186627, 26261251). This variant has not been identified 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	RCV000163461	SCV002534804	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-01	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000410914	SCV004017721	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2023-04-06	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV000410914	SCV004200369	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2024-03-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586583	SCV005076611	uncertain significance	not specified	2024-04-24	criteria provided, single submitter	clinical testing	Variant summary: RAD51D c.349T>A (p.Cys117Ser) results in a non-conservative amino acid change located in the DNA recombination and repair protein Rad51-like, C-terminal (IPR003593) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251350 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.349T>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Tung_2015, Song_2015). These report(s) 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. The following publications have been ascertained in the context of this evaluation (PMID: 26261251, 25186627). ClinVar contains an entry for this variant (Variation ID: 184247). Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV000410914	SCV005641830	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2024-06-20	criteria provided, single submitter	clinical testing