17-58692675-A-G

Position:

• chr17-58692675-A-G

Variant summary

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

The NM_058216.3(RAD51C):​c.32A>G​(p.Gln11Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: RAD51C NM_058216.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 6.88

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD51C	NM_058216.3	c.32A>G	p.Gln11Arg	missense_variant	1/9	ENST00000337432.9	NP_478123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD51C	ENST00000337432.9	c.32A>G	p.Gln11Arg	missense_variant	1/9	1	NM_058216.3	ENSP00000336701.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251450 Hom.: 0 AF XY: 0.00 AC XY: 0 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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727246

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 14, 2014	This variant is denoted RAD51C c.32A>G at the cDNA level, p.Gln11Arg (Q11R) at the protein level, and results in the change of a Glutamine to an Arginine (CAG>CGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD51C Gln11Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glutamine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. RAD51C Gln11Arg occurs at a position that is highly conserved across species and is located in a region required for Holliday junction resolution activity (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether RAD51C Gln11Arg is pathogenic or benign. We consider it to be a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 18, 2016	Variant summary: The c.32A>G variant affects a conserved nucleotide, resulting in amino acid change from Gln to Arg. 2/3 in-silico tools predict this variant to be damaging (SNPs&GO not captured due to low reliability index). 3/5 programs in Alamut predict that this variant results in the loss of a splice acceptor site. However, these predictions are not confirmed by experimental studies. This variant is not found in 126728 control chromosomes. In addition, a reputable clinical lab has classified this variant as VUS. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 26, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 20, 2023	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Fanconi anemia complementation group O Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 05, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 182842). This missense change has been observed in individual(s) with ovarian cancer (PMID: 26261251). This variant is present in population databases (rs730881937, gnomAD 0.0009%). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 11 of the RAD51C protein (p.Gln11Arg). -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

Jul 02, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.0082	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	23
DANN	Benign	0.90
DEOGEN2	Benign	0.028	T;T;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.57	T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.45	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	.;M;M
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.3	.;N;N
REVEL	Benign	0.19
Sift	Uncertain	0.023	.;D;D
Sift4G	Benign	0.13	T;T;D
Polyphen		0.93	.;P;.
Vest4		0.67
MutPred		0.42		Gain of MoRF binding (P = 0.017);Gain of MoRF binding (P = 0.017);Gain of MoRF binding (P = 0.017);
MVP		0.73
MPC		0.64
ClinPred		0.91	D
GERP RS		4.5
Varity_R		0.096
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs730881937; hg19: chr17-56770036;