rs375889604

Variant names:

• chr17-58692625-G-A
• rs375889604
• ENST00000482007.5:n.-19G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-58692625-G-A
• chr17-58692625-G-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The ENST00000482007.5(RAD51C):​n.-19G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,613,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: RAD51C ENST00000482007.5 non_coding_transcript_exon
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: -2.84
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 17-58692625-G-A is Benign according to our data. Variant chr17-58692625-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 378458.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD51C	NM_058216.3	c.-19G>A		5_prime_UTR_variant	Exon 1 of 9	ENST00000337432.9	NP_478123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD51C	ENST00000337432.9	c.-19G>A		5_prime_UTR_variant	Exon 1 of 9	1	NM_058216.3	ENSP00000336701.4

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152232 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 250768 AF XY: 0.0000221

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461294 Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12 AN XY: 726914

African (AFR) AF: 0.000448 AC: 15 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53260

Middle Eastern (MID) AF: 0.000365 AC: 2 AN: 5478

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111988

Other (OTH) AF: 0.0000994 AC: 6 AN: 60348

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152350 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74498

African (AFR) AF: 0.000289 AC: 12 AN: 41590

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000106

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Jan 08, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a G>A nucleotide substitution at the -19 position in the 5' untranslated region of the RAD51C gene. This variant is located distal to the Kozak consensus sequence (PMID: 3313277). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 8/282158 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may not be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Sep 16, 2020

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not specified Benign:2

Jan 05, 2016

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial ovarian cancer Uncertain:1

Dec 12, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.9
DANN	Benign	0.85
PhyloP100		-2.8
PromoterAI		-0.13	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=299/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs375889604; hg19: chr17-56769986;