rs771332058

chr17-58692660-T-Achr17-58692660-T-Cchr17-58692660-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_058216.3(RAD51C):c.17T>A(p.Phe6Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F6L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RAD51C NM_058216.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: -2.66

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05766493).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD51C	NM_058216.3	c.17T>A	p.Phe6Tyr	missense_variant	1/9	ENST00000337432.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD51C	ENST00000337432.9	c.17T>A	p.Phe6Tyr	missense_variant	1/9	1	NM_058216.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251416 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135904

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727234

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 10, 2022	This missense variant replaces phenylalanine with tyrosine at codon 6 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251416 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	Mar 09, 2022	The p.F6Y variant (also known as c.17T>A), located in coding exon 1 of the RAD51C gene, results from a T to A substitution at nucleotide position 17. The phenylalanine at codon 6 is replaced by tyrosine, an amino acid with highly similar properties. This amino acid position is poorly 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 11, 2015

This variant is denoted RAD51C c.17T>A at the cDNA level, p.Phe6Tyr (F6Y) at the protein level, and results in the change of a Phenylalanine to a Tyrosine (TTC>TAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD51C Phe6Tyr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Phenylalanine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. RAD51C Phe6Tyr occurs at a position that is not conserved and is located in the region required for Holliday junction resolution activity (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether RAD51C Phe6Tyr is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Fanconi anemia complementation group O Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 31, 2021

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 409849). This variant has not been reported in the literature in individuals affected with RAD51C-related conditions. This variant is present in population databases (rs771332058, gnomAD 0.0009%). This sequence change replaces phenylalanine, which is neutral and non-polar, with tyrosine, which is neutral and polar, at codon 6 of the RAD51C protein (p.Phe6Tyr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	0.20
Dann	Benign	0.56
DEOGEN2	Benign	0.0072	T;T;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.30	T;T;T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.058	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.46	T
Sift4G	Benign	1.0	T;T;D
Polyphen		0.0	.;B;.
Vest4		0.27
MutPred		0.27		Gain of phosphorylation at F6 (P = 0.0509);Gain of phosphorylation at F6 (P = 0.0509);Gain of phosphorylation at F6 (P = 0.0509);
MVP		0.21
MPC		0.26
ClinPred		0.024	T
GERP RS		-10
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.038
gMVP		0.097

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: rs771332058; hg19: chr17-56770021;