rs773998134

Positions:

• chr17-58692749-G-A
• chr17-58692749-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_058216.3(RAD51C):​c.106G>A​(p.Glu36Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E36G) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: RAD51C NM_058216.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 2.81

Genes affected

RAD51C (HGNC:9820): (RAD51 paralog C) This gene is a member of the RAD51 family. RAD51 family members are highly similar to bacterial RecA and Saccharomyces cerevisiae Rad51 and are known to be involved in the homologous recombination and repair of DNA. This protein can interact with other RAD51 paralogs and is reported to be important for Holliday junction resolution. Mutations in this gene are associated with Fanconi anemia-like syndrome. This gene is one of four localized to a region of chromosome 17q23 where amplification occurs frequently in breast tumors. Overexpression of the four genes during amplification has been observed and suggests a possible role in tumor progression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.35224378).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD51C	NM_058216.3	c.106G>A	p.Glu36Lys	missense_variant	1/9	ENST00000337432.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD51C	ENST00000337432.9	c.106G>A	p.Glu36Lys	missense_variant	1/9	1	NM_058216.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251458 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 30, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22451500, 25470109, 23117857, 21537932, 24139550, 34923718, 29484706) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 15, 2023	In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMID: 29484706 (2018), 24139550 (2013), 23117857 (2012), 21537932 (2011)). A published functional study reported that this variant does not significantly disrupt homology direct repair activity (PMID: 37253112 (2023)). The frequency of this variant in the general population, 0.000035 (4/113752 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 18, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 08, 2023	The p.E36K variant (also known as c.106G>A), located in coding exon 1 of the RAD51C gene, results from a G to A substitution at nucleotide position 106. The glutamic acid at codon 36 is replaced by lysine, an amino acid with similar properties. This alteration was originally identified in a Spanish female diagnosed with breast cancer at age 38 who had two relatives with breast cancer (Romero A et al. Breast Cancer Res. Treat. 2011 Oct;129(3):939-46). This cohort was later included with other Spanish breast and/or ovarian cancer families, and p.E36K was ultimately reported in 1/785 affected families (Osorio A et al. Hum. Mol. Genet. 2012 Jul;21(13):2889-98). This variant was also reported in 2/142 unrelated patients with breast and/or ovarian cancer who had either early onset cancer or a family history of breast/ovarian cancer (Goldmar L et al. BMC Cancer. 2013;13:484), and also reported in 1/34 Italian breast cancer patients (Guacci A et al. J Clin Lab Anal, 2018 Jul;32:e22418). In a homology-directed DNA repair (HDR) assay, this alteration showed a functionally normal read-out. (Hu C et al. Cancer Res, 2023 Aug;83:2557-2571). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

May 03, 2021

- -

Fanconi anemia complementation group O Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 16, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 36 of the RAD51C protein (p.Glu36Lys). This variant is present in population databases (rs773998134, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer and/or colorectal cancer (PMID: 34923718). ClinVar contains an entry for this variant (Variation ID: 216803). 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 not expected to disrupt RAD51C protein function. 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. -

Breast-ovarian cancer, familial, susceptibility to, 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 13, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.019	T;T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.043
FATHMM_MKL	Benign	0.76	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.35	T;T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	0.52	N;N;N
PrimateAI	Uncertain	0.61	T
Sift4G	Benign	0.68	T;T;T
Polyphen		0.027	.;B;.
Vest4		0.63
MutPred		0.36		Gain of ubiquitination at E36 (P = 0.0337);Gain of ubiquitination at E36 (P = 0.0337);Gain of ubiquitination at E36 (P = 0.0337);
MVP		0.70
MPC		0.27
ClinPred		0.26	T
GERP RS		3.7
Varity_R		0.079
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs773998134; hg19: chr17-56770110;