17-58695092-T-G

Position:

• chr17-58695092-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_058216.3(RAD51C):​c.307T>G​(p.Phe103Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAD51C NM_058216.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.08

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.81

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD51C	NM_058216.3	c.307T>G	p.Phe103Val	missense_variant	2/9	ENST00000337432.9	NP_478123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD51C	ENST00000337432.9	c.307T>G	p.Phe103Val	missense_variant	2/9	1	NM_058216.3	ENSP00000336701.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Genomics Laboratory, Virgen de la Arrixaca University Clinical Hospital

Jun 13, 2017

In the protein, it causes the change of phenylanine to valine in codon 103. This amino acid is located in the ATPase domain of the protein, which is highly conserved on the evolutionary scale. The results of the in silico studies show discrepancies regarding the pathogenicity of the variant (Mutation Taster: causing disease, SIFT: Tolerated, PolyPhen-2, likely pathogenic, A-GVGD: Class C45). The variant c.307T>G was detected in a bilateral Breast Cancer family and in a healthy control in heterozygosis (MAF: 0.003). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.061	T;T;.;T;T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Pathogenic	0.81	D;D;D;D;D
MetaSVM	Benign	-0.66	T
MutationAssessor	Pathogenic	3.3	.;M;M;.;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.3	.;D;D;D;.
REVEL	Uncertain	0.46
Sift	Benign	0.13	.;T;D;D;.
Sift4G	Benign	0.13	T;T;D;T;T
Polyphen		0.99	.;D;.;.;.
Vest4		0.83
MutPred		0.62		Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);.;.;
MVP		0.91
MPC		0.89
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1114167446; hg19: chr17-56772453;