rs531838785

chr17-58703225-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_058216.3(RAD51C):c.601C>G(p.Leu201Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000435 in 1,610,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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. L201P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: RAD51C NM_058216.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:1
• Conservation: PhyloP100: 1.52

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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08035803).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD51C	NM_058216.3	c.601C>G	p.Leu201Val	missense_variant	4/9	ENST00000337432.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD51C	ENST00000337432.9	c.601C>G	p.Leu201Val	missense_variant	4/9	1	NM_058216.3	P2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152186 Hom.: 0 Cov.: 31

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: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251262 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135814

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.00000343 AC: 5 AN: 1458148 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725714

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152304 Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1 AN XY: 74474

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 07, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal history of breast cancer and other cancers in published literature (Tung 2016, Mandelker 2017); This variant is associated with the following publications: (PMID: 26976419, 28873162, 14704354) -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 06, 2016	Variant summary: The RAD51C c.601C>G (p.Leu201Val) variant causes a missense change involving a non-conserved nucleotide with 3/4 in silico tools (SNPs&GO not captured here due to low reliability index) predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/121042 (1/60521), which does not exceed the estimated maximal expected allele frequency for a pathogenic RAD51C variant of 1/16000. A publication cites the variant in an affected individual with a classification of "unknown significance." Reputable databases and clinical diagnositic laboratories have not, to our knowledge, cited the variant of interest. Therefore, until additional clinical and/or functional studies become available, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)." -

Fanconi anemia complementation group O Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 29, 2023	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 201 of the RAD51C protein (p.Leu201Val). This variant is present in population databases (rs531838785, gnomAD 0.03%). This missense change has been observed in individual(s) with breast cancer and unspecified cancer (PMID: 26976419, 28873162). ClinVar contains an entry for this variant (Variation ID: 496506). 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	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

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

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 17, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 29, 2024	This alteration is classified as likely 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 06, 2023	This missense variant replaces leucine with valine at codon 201 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 observed in an individual affected with breast cancer (PMID: 26976419) and with unspecified advanced cancer (PMID: 28873162). This variant has been identified in 3/251262 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. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Dec 12, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	18
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0018	T;T;T;T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.81	T;T;T;T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.080	T;T;T;T
MetaSVM	Benign	-0.88	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.36	T
Sift4G	Benign	0.56	T;T;T;T
Polyphen		0.030	.;.;B;.
Vest4		0.33
MutPred		0.60		.;Gain of loop (P = 0.0851);Gain of loop (P = 0.0851);.;
MVP		0.67
MPC		0.23
ClinPred		0.15	T
GERP RS		5.8
Varity_R		0.19
gMVP		0.39

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

Other links and lift over

dbSNP: rs531838785; hg19: chr17-56780586;