17-58696719-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS1_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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:19 B:1
• Conservation: PhyloP100: 7.08

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 Likely_benign. Variant got -1 ACMG points.

• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome 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 gnomad4_exome. There are 110 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD51C	NM_058216.3	c.431T>C	p.Ile144Thr	missense_variant	3/9	ENST00000337432.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD51C	ENST00000337432.9	c.431T>C	p.Ile144Thr	missense_variant	3/9	1	NM_058216.3	P2

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152222 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.0000477 AC: 12 AN: 251478 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135912

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 SAS 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.: 0 Cov.: 31 AF XY: 0.000151 AC XY: 110 AN XY: 727236

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000163

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74364

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000412 Hom.: 0

Bravo AF: 0.000113

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:19 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:7

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 15, 2023	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. -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 21, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2023	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 (Prakash et al., 2022); 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, 36099300, 14704354) -
Uncertain significance, no assertion criteria provided	curation	Leiden Open Variation Database	Nov 02, 2014	Curator: Arleen D. Auerbach. Submitter to LOVD: Christine Rappaport. -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Breast-ovarian cancer, familial, susceptibility to, 3 Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 19, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 05, 2023	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]. -
Uncertain significance, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 05, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jul 22, 2016	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 27, 2022	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 patients 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 alteration was also identified in 1/1358 non-cancer control individuals in a study looking at cancer predisposition mutations in patients with multiple primary cancers (Pritchard AL et al. PLoS ONE 2018 Apr;13(4):e0194098). This amino acid position is well 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 13, 2022	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 (internally defined REVEL score threshold <= 0.5, PMID: 27666373). 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. -

Fanconi anemia complementation group O Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jul 22, 2016	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Carcinoma of colon Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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) “With Uncertain significance allele”, 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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

RAD51C-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 16, 2023

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

Uncertain significance, no assertion criteria provided

research

Reproductive Development, Murdoch Childrens Research Institute

Jan 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Uncertain	0.040
Cadd	Pathogenic	27
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	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.60	D;D;D;D;D
MetaSVM	Benign	-0.73	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	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	D
GERP RS		5.7
Varity_R		0.54
gMVP		0.78

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: rs28363307; hg19: chr17-56774080;