17-58696694-A-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_058216.3(RAD51C):c.406A>T(p.Met136Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000383 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

RAD51C
NM_058216.3 missense, splice_region

Scores

Splicing: ADA: 0.0005594

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:1

Conservation

PhyloP100: 2.52

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18198696).

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000383 (56/1461856) while in subpopulation EAS AF= 0.00139 (55/39688). AF 95% confidence interval is 0.00109. There are 0 homozygotes in gnomad4_exome. There are 31 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD51C	NM_058216.3 link	c.406A>T	p.Met136Leu	missense_variant, splice_region_variant	Exon 3 of 9	ENST00000337432.9	NP_478123.1	O43502-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD51C	ENST00000337432.9 link	c.406A>T	p.Met136Leu	missense_variant, splice_region_variant	Exon 3 of 9	1	NM_058216.3	ENSP00000336701.4		O43502-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251476

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000383

AC:

AN:

1461856

Hom.:

Cov.:

AF XY:

0.0000426

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00139

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Oct 04, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M136L variant (also known as c.406A>T), located in coding exon 3 of the RAD51C gene, results from an A to T substitution at nucleotide position 406. The methionine at codon 136 is replaced by leucine, an amino acid with highly similar properties. This variant has been identified in 41/12503 unselected Japanese colorectal cancer patients and in 78/23705 controls. (Fujita M et al. Clin Gastroenterol Hepatol, 2022 Sep;20:2132-2141.e9). This amino acid position is not 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. -

Feb 01, 2022

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Mar 24, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast-ovarian cancer, familial, susceptibility to, 3

Uncertain:2

Jun 16, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 04, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 136 of the RAD51C protein (p.Met136Leu). This variant is present in population databases (rs587780254, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with RAD51C-related conditions.Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (Variation ID: 128204). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated and.computational tools predict no significant impact on normal splicing. 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. -

not specified

Uncertain:1

Nov 30, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RAD51C c.406A>T (p.Met136Leu) results in a conservative amino acid change located in the ATP-binding domain (IPR020588) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00013 in 268236 control chromosomes (gnomAD and jMorp Japanese database). The observed variant frequency is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD51C causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (6.3e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.406A>T in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with a pathogenic variant have been reported via internal testing (BRCA1 c.3770_3771delAG, p.Glu1257GlyfsX9), providing supporting evidence for a benign role. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Microcephaly

Uncertain:1

Department of Pediatrics, Samsung Medical Center, Samsung Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Fanconi anemia complementation group O;C3150659:Breast-ovarian cancer, familial, susceptibility to, 3

Uncertain:1

Apr 07, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1

Sep 12, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as a pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 22975805) -

Fanconi anemia complementation group O

Uncertain:1

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 136 of the RAD51C protein (p.Met136Leu). This variant is present in population databases (rs587780254, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with RAD51C-related conditions. ClinVar contains an entry for this variant (Variation ID: 128204). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect RAD51C function (PMID: 37253112). 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. -

Hereditary breast ovarian cancer syndrome

Uncertain:1

May 01, 2019

Cancer Genomics Group, Japanese Foundation For Cancer Research

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.84

DEOGEN2

Benign

0.018

T;T;T;T;T

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.88

D;T;T;T;D

M_CAP

Benign

0.0055

MetaRNN

Benign

0.18

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.61

.;.;N;.;.

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.1

.;.;N;N;.

REVEL

Benign

0.085

Sift

Benign

0.20

.;.;T;T;.

Sift4G

Benign

1.0

T;T;T;T;T

Polyphen

0.0060

.;.;B;.;.

Vest4

0.42, 0.41

MutPred

0.64

.;Loss of methylation at K131 (P = 0.0725);Loss of methylation at K131 (P = 0.0725);.;.;

MVP

0.31

MPC

0.21

ClinPred

0.045

GERP RS

4.6

Varity_R

0.20

gMVP

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00056

dbscSNV1_RF

Benign

0.0060

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over