rs61758784

chr17-58695161-G-Achr17-58695161-G-Cchr17-58695161-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_058216.3(RAD51C):c.376G>A(p.Ala126Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00494 in 1,612,814 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A126V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0034 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (30 hom.)
• Consequence: RAD51C NM_058216.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:28
• Conservation: PhyloP100: 5.81

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 uncertain in NM_058216.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.012307972).
• BP6: Variant 17-58695161-G-A is Benign according to our data. Variant chr17-58695161-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 132721.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-58695161-G-A is described in Lovd as [Likely_benign]. Variant chr17-58695161-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00338 (514/152210) while in subpopulation NFE AF= 0.00559 (380/68008). AF 95% confidence interval is 0.00512. There are 3 homozygotes in gnomad4. There are 238 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD51C	NM_058216.3	c.376G>A	p.Ala126Thr	missense_variant	2/9	ENST00000337432.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD51C	ENST00000337432.9	c.376G>A	p.Ala126Thr	missense_variant	2/9	1	NM_058216.3	P2

Frequencies

GnomAD3 genomes AF: 0.00338 AC: 514 AN: 152092 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00559

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00352 AC: 879 AN: 250008 Hom.: 2 AF XY: 0.00367 AC XY: 496 AN XY: 135154

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00328

Gnomad ASJ exome AF: 0.00429

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00171

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.00541

Gnomad OTH exome AF: 0.00574

GnomAD4 exome AF: 0.00511 AC: 7459 AN: 1460604 Hom.: 30 Cov.: 31 AF XY: 0.00510 AC XY: 3706 AN XY: 726376

Gnomad4 AFR exome AF: 0.000957

Gnomad4 AMR exome AF: 0.00325

Gnomad4 ASJ exome AF: 0.00418

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00149

Gnomad4 FIN exome AF: 0.000525

Gnomad4 NFE exome AF: 0.00602

Gnomad4 OTH exome AF: 0.00474

GnomAD4 genome AF: 0.00338 AC: 514 AN: 152210 Hom.: 3 Cov.: 32 AF XY: 0.00320 AC XY: 238 AN XY: 74436

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.00393

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00559

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00593 Hom.: 4

Bravo AF: 0.00343

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00640 AC: 55

ExAC AF: 0.00348 AC: 422

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00654

EpiControl AF: 0.00610

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:28

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 06, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 14, 2020	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 03, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:7

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 09, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	RAD51C: BP4, BS2 -

Breast-ovarian cancer, familial, susceptibility to, 3 Benign:5

Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 10, 2023	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Oct 19, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Jun 10, 2016	- -

Hereditary cancer-predisposing syndrome Benign:4

Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Dec 01, 2017	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	May 20, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 16, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 28, 2014	This alteration is classified as 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 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Jun 10, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

May 15, 2019

- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The RAD51C p.Ala126Thr variant was identified in 70 of 11449 proband chromosomes (frequency: 0.006) from individuals or families with hereditary breast and ovarian cancer (Akbari_2010_20723205, Blanco_2014_25086635, Clague_2011_21980511, Coulet_2013_22725699, Jonson_2015_26740214, Kushnir_2012_23117857, Leeneer_2012_22370629, Lu_2012_22476429, Meindl_2009_20400964, Romero_2011_ 21537932, Scheckenbach_2014_24315737, Thompson_2012_21990120, Vuorela_2011_21750962, Wong_2011_21409391). The variant was also identified in dbSNP (ID: rs61758784) as “With other allele”, ClinVar (as likely benign by PreventionGenetics and Counsyl, as benign by Invitae, GeneDx, Ambry Genetics, Color Genomics, and Quest Diagnostics), Clinvitae (as benign and likely benign), LOVD 3.0 (9x), and Zhejiang Colon Cancer Database (2x). The variant was not identified in Cosmic or MutDB databases. The variant was identified in control databases in 955 of 275828 chromosomes (3 homozygous) at a frequency of 0.003462 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 28 of 23954 chromosomes (freq: 0.001169), Other in 31 (1 homozygous) of 6444 chromosomes (freq: 0.004811), Latino in 109 (1 homozygous) of 34292 chromosomes (freq: 0.003179), European (Non-Finnish) in 684 (1 homozygous) of 125890 chromosomes (freq: 0.005433), Ashkenazi Jewish in 43 of 10090 chromosomes (freq: 0.004262), European (Finnish) in 8 of 25752 chromosomes (freq: 0.000311), and South Asian in 52 of 30556 chromosomes (freq: 0.001702), while the variant was not observed in the East Asian populations. The variant is classified as a benign polymorphism in the literature (Akbari_2010_20723205, Clague_2011_21980511, Coulet_2013_22725699, Jonson_2015_26740214, Kushnir_2012_23117857, Leeneer_2012_22370629, Lu_2012_22476429, Meindl_2009_20400964, Osorio_2012_22451500). In vivo yeast functional studies have shown no detectable difference in expression versus the wild type allele (Clague_2011_21980511). In addition, Jonson (2015_26740214) has reported that the variant to be co-occurring in three individuals with a disease-causing RAD51C (c.945dupT), BRCA1 (p.Gln563Ter) or BRCA2 (c.5164_5165delAG) mutation, increasing the likelihood that the p.Ala126Thr variant does not have clinical significance. The p.Ala126Thr residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.016	T;T;T;.;T;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.012	T;T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.27	T
Sift4G	Benign	0.27	T;T;T;T;T;T
Polyphen		0.066	.;.;B;.;.;.
Vest4		0.48, 0.48, 0.19
MVP		0.75
MPC		0.31
ClinPred		0.021	T
GERP RS		3.4
Varity_R		0.17
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs61758784; hg19: chr17-56772522; COSMIC: COSV104591839; COSMIC: COSV104591839;