chr17-58695161-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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 (★★).

Frequency

Genomes: 𝑓 0.0034 ( 3 hom., cov: 32)
Exomes 𝑓: 0.0051 ( 30 hom. )

Consequence

RAD51C
NM_058216.3 missense

Scores

6
13

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:29

Conservation

PhyloP100: 5.81
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

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. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RAD51CNM_058216.3 linkc.376G>A p.Ala126Thr missense_variant Exon 2 of 9 ENST00000337432.9 NP_478123.1 O43502-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RAD51CENST00000337432.9 linkc.376G>A p.Ala126Thr missense_variant Exon 2 of 9 1 NM_058216.3 ENSP00000336701.4 O43502-1

Frequencies

GnomAD3 genomes
AF:
0.00338
AC:
514
AN:
152092
Hom.:
3
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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:29
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:8
-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Oct 09, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

RAD51C: BP4, BS2 -

Nov 03, 2021
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not specified Benign:7
-
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 14, 2020
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 03, 2014
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jun 10, 2021
Genetic Services Laboratory, University of Chicago
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 06, 2018
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Breast-ovarian cancer, familial, susceptibility to, 3 Benign:5
Jun 10, 2016
Counsyl
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 10, 2023
Myriad Genetics, Inc.
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jul 07, 2023
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 29, 2024
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 19, 2020
Genetics and Molecular Pathology, SA Pathology
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:4
Oct 16, 2015
Color Diagnostics, LLC DBA Color Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 01, 2017
True Health Diagnostics
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jul 28, 2014
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

May 20, 2020
Sema4, Sema4
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Fanconi anemia complementation group O Benign:3
Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 28, 2019
Mendelics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 10, 2016
Counsyl
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Breast and/or ovarian cancer Benign:1
May 15, 2019
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Malignant tumor of breast Benign:1
-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

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
MutationAssessor
Uncertain
2.3
.;.;M;M;.;.
PrimateAI
Benign
0.27
T
PROVEAN
Benign
-1.8
.;.;N;N;N;.
REVEL
Benign
0.10
Sift
Benign
0.14
.;.;T;D;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

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

Other links and lift over

dbSNP: rs61758784; hg19: chr17-56772522; COSMIC: COSV104591839; COSMIC: COSV104591839; API