17-58696719-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM1BS1_Supporting

The NM_058216.3(RAD51C):c.431T>C(p.Ile144Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000142 in 1,614,096 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. I144L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

RAD51C
NM_058216.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:20B:1

Conservation

PhyloP100: 7.08

Publications

16 publications found

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 Gene-Disease associations (from GenCC):

breast-ovarian cancer, familial, susceptibility to, 3
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
Fanconi anemia complementation group O
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
hereditary breast ovarian cancer syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

RAD51C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 39 uncertain in NM_058216.3

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000146 (213/1461874) while in subpopulation MID AF = 0.00295 (17/5768). AF 95% confidence interval is 0.00188. There are 0 homozygotes in GnomAdExome4. There are 110 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. 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.431T>C	p.Ile144Thr	missense_variant	Exon 3 of 9	ENST00000337432.9	NP_478123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD51C	ENST00000337432.9 link	c.431T>C	p.Ile144Thr	missense_variant	Exon 3 of 9	1	NM_058216.3	ENSP00000336701.4

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000477

AC:

AN:

251478

AF XY:

0.0000589

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000146

AC:

213

AN:

1461874

Hom.:

Cov.:

AF XY:

0.000151

AC XY:

110

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00295

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000163

AC:

181

AN:

1112006

Other (OTH)

AF:

0.000116

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000105

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41464

American (AMR)

AF:

0.000131

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000510

Hom.:

Bravo

AF:

0.000113

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:20Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:7

Nov 02, 2014

Leiden Open Variation Database

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:curation

Curator: Arleen D. Auerbach. Submitter to LOVD: Christine Rappaport. -

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 21, 2018

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 15, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMID: 25186627 (2015), 25470109 (2015), 26740214 (2016), 36293153 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/RAD51C)), and endometrial cancer (PMID: 36293153 (2022)). This variant is also reported in unaffected individuals (PMID: 26261251 (2015), 29641532 (2018), 36293153 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/RAD51C)). The frequency of this variant in the general population, 0.00024 (6/24968 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Mar 17, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate conflicting results with respect to homology-directed repair activity and binding to RAD51C partners (PMID: 37253112, 36099300); This variant is associated with the following publications: (PMID: 23117857, 25318351, 25470109, 26261251, 26740214, 21537932, 29522266, 20052722, 25186627, 30309722, 30924587, 33471991, 35402282, 35039523, 29641532, 36293153, 22538716, 28829762, 37306523, 34326862, 38511139, 35534704, 14704354, 37253112, 36099300) -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breast-ovarian cancer, familial, susceptibility to, 3

Uncertain:3Benign:1

Jul 05, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant previously detected in same tribe. This sequence change replaces isoleucine with threonine at codon 144 of the RAD51C protein (p.Ile144Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs28363307, ExAC 0.01%). This variant has been reported in individuals affected with ovarian and/or breast cancer (PMID: 22538716, 23117857, 26740214, 21537932, 25186627), and in a healthy control individual (PMID: 26261251). ClinVar contains an entry for this variant (Variation ID: 142840). In silico analysis supports that this missense variant has a deleterious effect on protein structure/function based on 9 pathogenic predictions from PolyPhen, DANN, EIGEN, FATHMMMKL, LIST-S2, MutationAssessor, MutationTaster, PrimateAI and SIFT vs 4 benign predictions from BayesDel_addAF, DEOGEN2, M-CAP and MVP. UniProt Variants classifies this variant as Benign, citing 3 articles (25394175, 20301753 and 20301575). Therefore, it has been classified as a Variant of Uncertain Significance. -

Apr 05, 2023

Myriad Genetics, Inc.

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -

Jul 22, 2016

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Mar 28, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:2

Nov 12, 2024

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.431T>C (p.Ile144Thr) results in a non-conservative amino acid change located in the Rad51-like, C-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 1614096 control chromosomes. The observed variant frequency is approximately 2.27 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). c.431T>C has been reported in the literature in individuals affected with Hereditary Breast And/or Ovarian Cancer Syndrome (e.g., Bu_2022, Jonson_2016, Kushnir_2012, Lim_2022, Loveday_2012, Tung_2015, Weitzel_2019). These data indicate that the variant may be associated with disease. Published functional studies demonstrate conflicting results with respect to homology-directed repair activity. The variant was HR proficient in Chinese hamster and MCF10A cells, but HR deficient in U2OS cells (examples: Hu_2023, and Prakash_2022). The following publications have been ascertained in the context of this evaluation (PMID: 36293153, 26740214, 23117857, 35039523, 22538716, 25186627, 31206626, 36099300, 37253112). ClinVar contains an entry for this variant (Variation ID: 142840). Based on the evidence outlined above, the variant was classified asVUS-possibly benign. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:2

May 14, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces isoleucine with threonine at codon 144 of the RAD51C protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 21537932, 22538716, 23117857, 25470109, 26261251, 26740214), ovarian cancer (PMID: 36099300) and endometrial cancer (PMID: 36293153). In a large breast cancer case-control study, this variant has been identified in 11/60466 cases and 16/53461 controls (PMID: 33471991). This variant has also been identified in four women older than age 70 years with no personal history of cancer (FLOSSIES; https://whi.color.com/). This variant has been identified in 16/282878 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. -

Jul 16, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.I144T variant (also known as c.431T>C), located in coding exon 3 of the RAD51C gene, results from a T to C substitution at nucleotide position 431. The isoleucine at codon 144 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in individuals with personal and/or family histories of breast and/or ovarian cancer (Loveday C et al. Nat. Genet. 2012 May;44:475-6; author reply 476; Kushnir A et al. Breast Cancer Res. Treat. 2012 Dec;136:869-74; Tung N et al. Cancer. 2015 Jan;121:25-33; Jønson L et al. Breast Cancer Res. Treat. 2016 Jan;155:215-22). However, this alteration was not detected in 3429 patients with invasive epithelial ovarian cancer but was reported in 1 of 2772 controls (Song H et al. J. Clin. Oncol. 2015 Sep;33:2901-7). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Fanconi anemia complementation group O

Uncertain:2

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 144 of the RAD51C protein (p.Ile144Thr). This variant is present in population databases (rs28363307, gnomAD 0.02%). This missense change has been observed in individual(s) with ovarian and/or breast cancer (PMID: 21537932, 22538716, 23117857, 25186627, 26261251, 26740214). ClinVar contains an entry for this variant (Variation ID: 142840). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt RAD51C protein function with a negative predictive value of 80%. 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. -

Jul 22, 2016

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

Carcinoma of colon

Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The RAD51C p.Ile144Thr variant was identified in 5 of 12902 proband chromosomes (frequency: 0.0004) from Danish, Ashkenazi Jewish, and British, individuals or families with HBOC (with or without breast cancer), or BRCA1/2 negative ovarian cancer and was identified in 1 of 7856 control chromosomes (frequency: 0.0001) from healthy individuals (Jonson 2015, Kushnir 2012, Loveday 2012, Song 2015, Yorczyk 2015). The variant was identified in dbSNP (ID: rs28363307) â€šÃ„ÃºWith Uncertain significance alleleâ€šÃ„Ã¹, ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, Invitae, Counsyl, and Color Genomics Inc.), Clinvitae (4x), LOVD 3.0 (1x), and was not identified in Cosmic and MutDB databases. The variant was also identified in control databases in 16 of 277234 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 6 of 24034 chromosomes (freq: 0.0003), and European Non-Finnish in 10 of 126720 chromosomes (freq: 0.00008); it was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Ile144 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Thr variant may impact the protein; however, this information is not predictive enough to assume 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 the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

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

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

RAD51C-related disorder

Uncertain:1

Feb 16, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The RAD51C c.431T>C variant is predicted to result in the amino acid substitution p.Ile144Thr. This variant has been reported in individuals with breast and/or ovarian cancer (Loveday et al. 2012. PubMed ID: 22538716; Jønson et al. 2016. PubMed ID: 26740214; Kushnir A et al 2012. PubMed ID: 23117857; Sopik V et al. 2015. PubMed ID: 25470109; Bu et al. 2022. PubMed ID: 36293153), but has not been reported in association with Fanconi anemia. This variant is reported in 0.0077% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org) and has been interpreted as variant of uncertain significance in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/142840/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Premature ovarian insufficiency

Uncertain:1

Jan 10, 2018

Reproductive Development, Murdoch Childrens Research Institute

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Uncertain

0.029

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.048

T;T;T;T;T

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.96

D;D;D;D;D

M_CAP

Benign

0.014

MetaRNN

Uncertain

0.60

D;D;D;D;D

MetaSVM

Benign

-0.73

MutationAssessor

Uncertain

2.4

.;.;M;.;.

PhyloP100

7.1

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.5

.;.;D;D;.

REVEL

Uncertain

0.31

Sift

Benign

0.078

.;.;T;D;.

Sift4G

Uncertain

0.0070

D;T;T;D;D

Polyphen

0.89

.;.;P;.;.

Vest4

0.87

MVP

0.79

MPC

0.85

ClinPred

0.70

GERP RS

5.7

Varity_R

0.54

gMVP

0.78

Mutation Taster

=22/78

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over