NM_058216.3:c.18C>A

Variant names:

• chr17-58692661-C-A
• rs774685897
• NM_058216.3:c.18C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_058216.3(RAD51C):​c.18C>A​(p.Phe6Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F6C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RAD51C NM_058216.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: -4.26
• Publications: 1 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05862412).

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.18C>A	p.Phe6Leu	missense	Exon 1 of 9	NP_478123.1
	RAD51C	NM_002876.4		c.18C>A	p.Phe6Leu	missense	Exon 1 of 2	NP_002867.1
	RAD51C	NR_103872.2		n.60C>A		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.18C>A	p.Phe6Leu	missense	Exon 1 of 9	ENSP00000336701.4
	RAD51C	ENST00000421782.3	TSL:1	c.18C>A	p.Phe6Leu	missense	Exon 1 of 2	ENSP00000391450.2
	RAD51C	ENST00000482007.5	TSL:1	n.18C>A		non_coding_transcript_exon	Exon 1 of 8	ENSP00000433332.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461862 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727234

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: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Hereditary cancer-predisposing syndrome (2)
-	1	-	Fanconi anemia complementation group O (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.11
DANN	Benign	0.65
DEOGEN2	Benign	0.0049	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N
PhyloP100		-4.3
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.022
Sift	Benign	0.23	T
Sift4G	Benign	0.49	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.26		Gain of MoRF binding (P = 0.0989)
MVP		0.29
MPC		0.26
ClinPred		0.28	T
GERP RS		-10
PromoterAI		-0.17	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.028
gMVP		0.13
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs774685897; hg19: chr17-56770022;