chr17-58703280-T-C

Position:

chr17-58703280-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_058216.3(RAD51C):c.656T>C(p.Leu219Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000497 in 1,610,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L219L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

RAD51C
NM_058216.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:8

Conservation

PhyloP100: 6.68

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.8

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD51C	NM_058216.3 linkuse as main transcript	c.656T>C	p.Leu219Ser	missense_variant	4/9	ENST00000337432.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD51C	ENST00000337432.9 linkuse as main transcript	c.656T>C	p.Leu219Ser	missense_variant	4/9	1	NM_058216.3	P2	O43502-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251286

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135818

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000480

AC:

AN:

1458276

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

725698

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00000610

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 3

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Feb 27, 2023	The RAD51C c.656T>C (p.Leu219Ser) missense change has a maximum subpopulation frequency of 0.0029% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and functional studies suggest that this variant affects RAD51C function (PMID: 22451500, 25292178). This variant has been reported in individuals with a personal and/or family history of breast and ovarian cancer (PMID: 22451500, 25086635). This variant is absent in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with Fanconi anemia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 03, 2024	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 25292178, 22451500]. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal and/or family history of breast, ovarian, or colorectal cancer (Osorio et al., 2012; Blanco et al., 2014; Guindalini et al., 2022; Mikaeel et al., 2022; Anwaar et al., 2023); Published functional studies are inconclusive: variant unable to restore wild-type levels of RAD51 foci formation in RAD51C-deficient fibroblasts, but RAD51C protein levels were not evaluated in this study; increased sensitivity to Poly (ADP-ribose) polymerase 1 (PARP1) inhibitors compared to wild-type, failure to suppress G2/M accumulation, but ability to retain stability, and conflicting results on effect on homologous recombination activity (Osorio et al., 2012; Somyajit et al., 2015; Prakash et al., 2022; Hu et al., 2023); This variant is associated with the following publications: (PMID: 25470109, 23117857, 28829762, 22451500, 25086635, 25154786, 25292178, 34761457, 36099300, 37253112, 35264596, 36969410, 14704354) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 17, 2018	- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 03, 2023	This missense variant replaces leucine with serine at codon 219 of the RAD51C protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported conflicting results. One study has shown the mutant protein to exhibit reduced homologous recombination activity, reduced ability to form RAD51C foci, and resulted in abnormal cell cycle progression (PMID:22451500, 25292178). Another study has shown that the mutant protein retains near normal homologous recombination activity, with reduced binding to RAD51D (13% of normal levels) and to RAD51B and XRCC3 (over 60% of normal levels) (PMID: 36099300). This variant has been reported in an individual affected with breast cancer with family history of breast cancer and ovarian cancer (PMID: 22451500) and in an individual affected with breast cancer or ovarian cancer (PMID: 23117857). It has also been reported in an individual affected with ovarian cancer, whose sister carries this variant and is unaffected with cancer (PMID: 25086635). This variant has been identified in 2/251286 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 27, 2023	The p.L219S variant (also known as c.656T>C), located in coding exon 4 of the RAD51C gene, results from a T to C substitution at nucleotide position 656. The leucine at codon 219 is replaced by serine, an amino acid with dissimilar properties. In one study, this variant was identified in a Spanish breast and ovarian cancer family and was absent in 550 general population controls (Osorio A et al. Hum. Mol. Genet. 2012 Jul;21:2889-98). When expressed in RAD51C-deficient cells, this variant was not able to restore normal function. This alteration was also reported in a Spanish female diagnosed with ovarian cancer at age 44 and having a family history of breast cancer and prostate cancer (Blanco A et al. Breast Cancer Res. Treat. 2014 Aug;147:133-43). The p.L219S variant was analyzed for homologous recombination (HR) efficiency using a GFP reporter and exhibited significantly reduced HR frequency (Somyajit K et al. Carcinogenesis. 2015 Jan;36:13-24). Authors also demonstrated that this variant displayed 3-fold sensitivity toward PARP inhibitors using CL-V4B cells incubated with 4-ANI. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 07, 2024

Variant summary: RAD51C c.656T>C (p.Leu219Ser) 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. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251286 control chromosomes (gnomAD). c.656T>C has been reported in the literature in individuals affected with breast, ovarian, or colorectal cancer without evidence of cosegregation with disease (e.g. Osorio_2012, Blanco_2014, Mikaeel_2022, de Oliveira_2022, Guindalini_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Publications report experimental evidence evaluating an impact on protein function. One study found that the variant resulted in a significant reduction in RAD51 foci-positive cells (Osorio_2012), while another study found that the variant did not result in a deleterious effect on homology-directed repair activity (Hu_2023). The following publications have been ascertained in the context of this evaluation (PMID: 22451500, 25086635, 34761457, 35534704, 35264596, 37253112). ClinVar contains an entry for this variant (Variation ID: 232604). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

Dec 31, 2023

- -

Fanconi anemia complementation group O

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 219 of the RAD51C protein (p.Leu219Ser). This variant is present in population databases (rs201529791, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of RAD51C-related conditions (PMID: 22451500, 25086635). ClinVar contains an entry for this variant (Variation ID: 232604). 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 expected to disrupt RAD51C protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects RAD51C function (PMID: 22451500, 25292178). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.051

T;T;T;T

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.81

T;T;T;T

M_CAP

Benign

0.083

MetaRNN

Pathogenic

0.80

D;D;D;D

MetaSVM

Uncertain

0.36

MutationAssessor

Uncertain

2.8

.;.;M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.5

.;.;D;D

REVEL

Uncertain

0.61

Sift

Uncertain

0.016

.;.;D;D

Sift4G

Uncertain

0.032

D;D;D;D

Polyphen

1.0

.;.;D;.

Vest4

0.97, 0.98

MutPred

0.65

.;Gain of helix (P = 0.0022);Gain of helix (P = 0.0022);.;

MVP

0.98

MPC

0.73

ClinPred

0.96

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.88

gMVP

0.85

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

Publications

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over