rs786201848

chr17-58703245-T-A

Variant summary

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

The NM_058216.3(RAD51C):c.621T>A(p.His207Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000756 in 1,455,554 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. H207R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: RAD51C NM_058216.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 1.02

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=0.19310379).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD51C	NM_058216.3	c.621T>A	p.His207Gln	missense_variant	4/9	ENST00000337432.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD51C	ENST00000337432.9	c.621T>A	p.His207Gln	missense_variant	4/9	1	NM_058216.3	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251246 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135786

Gnomad AFR exome AF: 0.00

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: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000756 AC: 11 AN: 1455554 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 724512

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000994

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000659 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 12, 2023	The p.H207Q variant (also known as c.621T>A), located in coding exon 4 of the RAD51C gene, results from a T to A substitution at nucleotide position 621. The histidine at codon 207 is replaced by glutamine, an amino acid with highly similar properties. This variant was reported in 3/60466 breast cancer cases and in 1/53461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This alteration was detected in 2/5589 German BRCA1/2-negative probands with breast cancer. (Hauke J et al. Cancer Med, 2018 04;7:1349-1358). This alteration demonstrated retained homology-directed repair (HDR) activity in one functional study (Hu C et al. Cancer Res, 2023 May;:). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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	Jul 06, 2023	This missense variant replaces histidine with glutamine at codon 207 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 2 individuals affected with breast or ovarian cancer (PMID: 29522266) and in a breast cancer case-control meta-analysis in 3/60463 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID RAD51C_000154). This variant has been identified in 3/251246 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. -

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

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	May 19, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 10, 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]. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Mar 27, 2019

- -

Fanconi anemia complementation group O Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 207 of the RAD51C protein (p.His207Gln). This variant is present in population databases (rs786201848, gnomAD 0.003%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 29522266). ClinVar contains an entry for this variant (Variation ID: 184991). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	19
Dann	Benign	0.96
DEOGEN2	Benign	0.022	T;T;T;T
Eigen	Benign	0.013
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.75	T;T;T;T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	0.86	D;D
PrimateAI	Uncertain	0.56	T
Sift4G	Benign	0.41	T;T;T;T
Polyphen		0.035	.;.;B;.
Vest4		0.36, 0.39
MutPred		0.58		.;Loss of sheet (P = 0.007);Loss of sheet (P = 0.007);.;
MVP		0.56
MPC		0.24
ClinPred		0.22	T
GERP RS		4.7
Varity_R		0.34
gMVP		0.55

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: rs786201848; hg19: chr17-56780606;