17-58732524-A-G

Position:

• chr17-58732524-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_058216.3(RAD51C):​c.1006A>G​(p.Thr336Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAD51C NM_058216.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.38

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]

RAD51C (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1802583).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD51C	NM_058216.3	c.1006A>G	p.Thr336Ala	missense_variant	8/9	ENST00000337432.9	NP_478123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD51C	ENST00000337432.9	c.1006A>G	p.Thr336Ala	missense_variant	8/9	1	NM_058216.3	ENSP00000336701.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 05, 2021

The p.T336A variant (also known as c.1006A>G), located in coding exon 8 of the RAD51C gene, results from an A to G substitution at nucleotide position 1006. The threonine at codon 336 is replaced by alanine, an amino acid with similar properties. A different alteration at this position, p.T336P, has been reported in 1 of 3,429 patients with invasive epithelial ovarian cancer (EOC) and was not seen in any of the 2,772 controls or 2,000 additional unaffected women who were BRCA1/BRCA2 mutation-negative (Song H et al, J. Clin. Oncol. 2015 Sep; 33(26):2901-7). 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-ovarian cancer, familial, susceptibility to, 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 20, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.019	T;T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.053
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.53	T;T
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	.;L
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.6	.;N
REVEL	Benign	0.076
Sift	Benign	0.19	.;T
Sift4G	Benign	0.18	T;T
Polyphen		0.0010	.;B
Vest4		0.21
MutPred		0.46		Loss of ubiquitination at K333 (P = 0.0863);Loss of ubiquitination at K333 (P = 0.0863);
MVP		0.66
MPC		0.23
ClinPred		0.60	D
GERP RS		4.8
Varity_R		0.098
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs772344354; hg19: chr17-56809885;