17-58692646-G-T

Variant names:

• chr17-58692646-G-T
• rs769053886
• NM_058216.3:c.3G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_058216.3(RAD51C):​c.3G>T​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,790 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 Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: RAD51C NM_058216.3 start_lost
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: -0.131
• Publications: 4 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: Uncertain_significance. The variant received 2 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 10 codons. Genomic position: 58692671. Lost 0.025 part of the original CDS.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_058216.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD51C	NM_058216.3	MANE Select	c.3G>T	p.Met1?	start_lost	Exon 1 of 9	NP_478123.1
	RAD51C	NM_002876.4		c.3G>T	p.Met1?	start_lost	Exon 1 of 2	NP_002867.1
	RAD51C	NR_103872.2		n.45G>T		non_coding_transcript_exon	Exon 1 of 8

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD51C	ENST00000337432.9	TSL:1 MANE Select	c.3G>T	p.Met1?	start_lost	Exon 1 of 9	ENSP00000336701.4
	RAD51C	ENST00000421782.3	TSL:1	c.3G>T	p.Met1?	start_lost	Exon 1 of 2	ENSP00000391450.2
	RAD51C	ENST00000482007.5	TSL:1	n.3G>T		non_coding_transcript_exon	Exon 1 of 8	ENSP00000433332.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461790 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727192

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

May 30, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Initiation codon variant in a gene for which a downstream in-frame ATG could serve as an alternate initiator codon, with published functional studies reporting the shortened product to retain wild-type function (French et al., 2003); Observed in an individual with breast cancer (Kraus et al., 2017); This variant is associated with the following publications: (PMID: 14704354, 22167183, 12966089, 25292178, 27616075)

May 08, 2017

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The RAD51C c.3G>T (p.Met1Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide that alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). The human gene for RAD51C, has two potential start codons, 27 base pairs apart, neither of which is an ideal sequence context compared with the Kozak consensus (French_TheJofBioChem_2003). A functional study showed that a cDNA with a 5 truncation intended to delete the first ATG codon, resulted in a protein that maintained its ability to complement the mitomycin-C sensitivity to a very similar level to the WT in a RAD51C-deficient cell line through the use of the adjacent ATG downstream in the sequence (data not shown)(French_TheJofBioChem_2003). The variant of interest was absent in a large, broad control population, ExAC in 120822 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS, although a benign effect for this variant cannot be ruled out.

Hereditary cancer-predisposing syndrome Uncertain:2

Jan 07, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant affects the translation start codon of the RAD51C gene and may result in an absent or non-functional protein product. However, an in-frame methionine 9 codons downstream may function as an alternative start codon and is located before the first known functional domain (RAD51B/RAD51D/XRCC3 interacting domain at amino acids 79-136) of the RAD51C protein. A functional study has shown that the RAD51C protein produced from this downstream methionine can function similarly to the wild type protein (PMID: 12966089). This variant has been reported in an individual affected with breast cancer (PMID: 27616075). This variant has not been identified 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.

Jul 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M1? variant (also known as c.3G>T) is located in coding exon 1 of the RAD51C gene and results from a G to T substitution at nucleotide position 3. This alters the methionine residue at the initiation codon. This alteration was reported as a variant of unknown significance in a woman with breast cancer diagnosed at age 67 from a cohort of 581 German high risk breast/ovarian cancer patients (Kraus C et al. Int. J. Cancer 2017 Jan;140(1):95-102). Variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame; however, there is an in-frame methionine 9 amino acids from the initiation site, which may result in N-terminal truncation of unknown functional significance. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Fanconi anemia complementation group O;C3150659:Breast-ovarian cancer, familial, susceptibility to, 3 Uncertain:1

Mar 04, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Fanconi anemia complementation group O Uncertain:1

Oct 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the RAD51C mRNA. The next in-frame methionine is located at codon 10. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with breast cancer (PMID: 27616075). ClinVar contains an entry for this variant (Variation ID: 216798). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.84
DANN	Benign	0.65
DEOGEN2	Benign	0.0051	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.051	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.13
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.16
Sift	Benign	0.62	T
Sift4G	Benign	0.14	T
Polyphen		0.0	B
Vest4		0.26
MutPred		0.97		Gain of catalytic residue at M1 (P = 0.0101)
MVP		0.61
ClinPred		0.035	T
GERP RS		-1.1
PromoterAI		-0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.035
gMVP		0.25
Mutation Taster		=157/43	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs769053886; hg19: chr17-56770007;