NM_058216.3:c.890T>C

Variant names:

• chr17-58720798-T-C
• rs143026267
• NM_058216.3:c.890T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_058216.3(RAD51C):​c.890T>C​(p.Leu297Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000279 in 1,611,706 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. L297F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: RAD51C NM_058216.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:14 B:1
• Conservation: PhyloP100: 4.17
• Publications: 2 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 41 uncertain in NM_058216.3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD51C	NM_058216.3	c.890T>C	p.Leu297Pro	missense_variant	Exon 6 of 9	ENST00000337432.9	NP_478123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD51C	ENST00000337432.9	c.890T>C	p.Leu297Pro	missense_variant	Exon 6 of 9	1	NM_058216.3	ENSP00000336701.4

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152214 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000319 AC: 8 AN: 251048 AF XY: 0.0000221

Gnomad AFR exome AF: 0.000493

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1459492 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726194

African (AFR) AF: 0.000628 AC: 21 AN: 33426

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53032

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5418

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110636

Other (OTH) AF: 0.00 AC: 0 AN: 60292

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152214 Hom.: 0 Cov.: 31 AF XY: 0.000134 AC XY: 10 AN XY: 74366

African (AFR) AF: 0.000579 AC: 24 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000114 Hom.: 0

Bravo AF: 0.000193

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:14 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Dec 01, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 24, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RAD51C c.890T>C (p.Leu297Pro) variant has been reported in the published literature in individuals with sporadic pancreatic cancer (PMID: 28767289 (2017)) and history of Lynch syndrome-associated cancer and/or polyps (PMID: 25980754 (2015)). It has also been observed in a cohort of individuals with prostate cancer and reportedly healthy individuals (PMID: 32832836 (2020)). The frequency of this variant in the general population, 0.00052 (13/24946 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.

Aug 06, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate homology-directed repair activity comparable to wild-type (PMID: 37253112); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28767289, 34923718, 25980754, 14704354, 37253112)

Hereditary cancer-predisposing syndrome Uncertain:3

Jul 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L297P variant (also known as c.890T>C), located in coding exon 6 of the RAD51C gene, results from a T to C substitution at nucleotide position 890. The leucine at codon 297 is replaced by proline, an amino acid with similar properties. This alteration was identified in a cohort of patients with pancreatic cancer or other periampullary neoplasms tested for hereditary cancer risk via a multi-gene panel. (Shindo K et al. J Clin Oncol, 2017 Oct;35:3382-3390). This variant was identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). In a homology-directed DNA repair (HDR) assay, this alteration showed a functionally normal read-out (Hu C et al. Cancer Res, 2023 Aug;83:2557-2571). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

Oct 12, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces leucine with proline at codon 297 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 one individual each affected with triple-negative breast cancer (https://austinpublishinggroup.com/cancer-clinical-research/fulltext/cancer-v5-id1082.pdf), Lynch syndrome-associated cancer and/or polyps (PMID: 25980754) and gallbladder cancer (PMID: 28767289). This variant has been identified in 13/282450 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.

Sep 10, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

Breast-ovarian cancer, familial, susceptibility to, 3 Uncertain:2 Benign:1

Sep 06, 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.

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].

Mar 29, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Uncertain:2

Apr 15, 2022

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.890T>C (p.Leu297Pro) results in a non-conservative amino acid change located in the DNA recombination and repair protein Rad51-like, C-terminal domain (IPR013632) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251048 control chromosomes, predominantly at a frequency of 0.00049 within the African or African-American subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.890T>C has been reported in the literature as a VUS in settings of multigene panel testing of individuals affected with/undergoing testing for Lynch syndrome, apparently sporadic pancreatic cancer (example, Yurgelun_2015, Shindo_2017) and in settings of integrated genomic profiling for patients with cancer (example, Beaubier_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome/RAD51C-related disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

Oct 31, 2018

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Fanconi anemia complementation group O Uncertain:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 297 of the RAD51C protein (p.Leu297Pro). This variant is present in population databases (rs143026267, gnomAD 0.05%). This missense change has been observed in individual(s) with gall bladder adenocarcinoma and an individual undergoing testing for Lynch syndrome (PMID: 25980754, 28767289). ClinVar contains an entry for this variant (Variation ID: 186828). 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 expected to disrupt RAD51C protein function with a positive 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.

Sep 06, 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.

Fanconi anemia complementation group O;C3150659:Breast-ovarian cancer, familial, susceptibility to, 3 Uncertain:1

Mar 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RAD51C-related disorder Uncertain:1

Jan 02, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The RAD51C c.890T>C variant is predicted to result in the amino acid substitution p.Leu297Pro. This variant has been reported in an individual with non-pancreatic ductal adenocarcinoma of the gallbladder (Table A2, Shindo et al. 2017. PubMed ID: 28767289), an individual with ovarian cancer (Table S1, Boni et al. 2022. PubMed ID: 34923718), and in a patient undergoing genetic testing for Lynch syndrome (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754). This variant is reported in 0.052% of alleles in individuals of African descent in gnomAD and has been interpreted as variant of uncertain significance in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/186828/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.050	T;T;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.44
LIST_S2	Benign	0.76	T;T;T
M_CAP	Benign	0.068	D
MetaRNN	Uncertain	0.63	D;D;D
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.0	.;M;.
PhyloP100		4.2
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.0	.;D;.
Sift	Pathogenic	0.0	.;D;.
Sift4G	Benign	0.065	T;D;D
Vest4		0.73
ClinPred		0.91	D
GERP RS		5.2
Varity_R		0.94
gMVP		0.90
Mutation Taster		=43/57	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs143026267; hg19: chr17-56798159;