rs577852020

chr17-58734188-G-Achr17-58734188-G-Cchr17-58734188-G-T

Variant summary

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

The NM_058216.3(RAD51C):c.1097G>A(p.Arg366Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,026 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R366W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

RAD51C
NM_058216.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:7B:1

Conservation

PhyloP100: 3.83

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:

LOC105371843 (HGNC:):

LOC105371843 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD51C	NM_058216.3 linkuse as main transcript	c.1097G>A	p.Arg366Gln	missense_variant	9/9	ENST00000337432.9
LOC105371843	XR_007065866.1 linkuse as main transcript	n.81-9763C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD51C	ENST00000337432.9 linkuse as main transcript	c.1097G>A	p.Arg366Gln	missense_variant	9/9	1	NM_058216.3	P2	O43502-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152050

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249618

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134818

show subpopulations

Gnomad AFR exome

AF:

0.0000626

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.00

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:

0.00000685

AC:

AN:

1460858

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726610

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000496

Hom.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:7Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 07, 2022	The frequency of this variant in the general population, 0.000012 (3/249618 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant is described to be hypomorphic resulting in partial loss of function (PMID: 25292178 (2015), 22167183 (2012)). Additionally, the variant was reported in an individual with familial breast and/or ovarian cancer (PMID: 20400964 (2010)). Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 15, 2023	Observed in at least one family with breast cancer and segregated with disease in two affected relatives; however, tumor analysis from one individual demonstrated no loss of heterozygosity (Meindl et al., 2010; Gevensleben et al., 2014); Published functional studies demonstrate reduced homologous recombination activity compared to wild-type, increased sensitivity to PARP inhibitors, and moderate sensitivity to DNA damaging agents, but no significant difference in RAD51 foci formation or interaction with RAD51B, RAD51D, XRCC2, or XRCC3 (Meindl et al., 2010; Somyajit et al., 2012; Somyajit et al., 2015; Mishra et al., 2018; Prakash et al., 2022); 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: 25470109, 24993905, 25292178, 26740214, 20952512, 20400964, 14704354, 12966089, 36099300, 31567591, 29158291, 28829762, 34910513, 36562461, 22167183, 21537932) -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 23, 2023	This missense variant replaces arginine with glutamine at codon 366 of the RAD51C protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported conflicting findings for this variant for which some have reported hypomorphic or partial loss-of-function (PMID: 20400964, 22167183, 25292178), while others reported no impact on normal binding to RAD51 paralogs, sensitivity to cisplatin and Olaparib treatment and function in a homology-directed repair assay (PMID: 36099300, 37253112). This variant has been reported in several individuals affected with personal or family history of breast or ovarian cancer (PMID: 20400964, 23117857, 25470109). This variant also has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 2/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID RAD51C_000025). This variant has been identified in 3/249618 chromosomes 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 01, 2022	The p.R366Q variant (also known as c.1097G>A), located in coding exon 9 of the RAD51C gene, results from a G to A substitution at nucleotide position 1097. The arginine at codon 366 is replaced by glutamine, an amino acid with highly similar properties. In a study of 1100 German high-risk breast and/or ovarian cancer families, this alteration was detected in one family (Meindl A et al. Nat. Genet., 2010 May;42:410-4). Another study detected this alteration in 1/492 breast cancer patients with family history of breast and/or ovarian cancer (Romero A et al. Breast Cancer Res. Treat., 2011 Oct;129:939-46). Functional studies have shown a reduction in homologous recombination activity from this alteration compared to wild-type protein (Somyajit K et al. Carcinogenesis, 2015 Jan;36:13-24). In another study, this alteration was shown to have reduced protein levels in the nucleus as compared to wild-type protein, but no change in protein levels in the mitochondria (Mishra A et al. Mol. Cell. Biol., 2018 02;38). This alteration was identified in a cohort of individuals with at least 3 primary melanoma diagnoses (Li C et al. Melanoma Res, 2020 06;30:247-251). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified

Uncertain:1Benign:1

Likely benign, no assertion criteria provided	curation	Leiden Open Variation Database	Nov 02, 2014	Curator: Arleen D. Auerbach. Submitter to LOVD: Johan den Dunnen. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Ovarian cancer

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Jan 01, 2022

- -

Fanconi anemia complementation group O

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 366 of the RAD51C protein (p.Arg366Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast cancer (PMID: 20400964). ClinVar contains an entry for this variant (Variation ID: 420041). 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 affects RAD51C function (PMID: 20400964, 22167183). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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

Jun 16, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.065

BayesDel_noAF

Benign

-0.14

Cadd

Uncertain

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.14

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.84

M_CAP

Benign

0.015

MetaRNN

Uncertain

0.66

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.3

MutationTaster

Benign

0.74

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.70

REVEL

Benign

0.22

Sift

Benign

0.031

Sift4G

Uncertain

0.037

Polyphen

1.0

Vest4

0.75

MutPred

0.21

Loss of loop (P = 0.0203);

MVP

0.83

MPC

0.29

ClinPred

0.29

GERP RS

3.1

Varity_R

0.047

gMVP

0.32

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

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