rs61758784

Variant names:

• chr17-58695161-G-A
• rs61758784
• NM_058216.3:c.376G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-58695161-G-A
• chr17-58695161-G-C
• chr17-58695161-G-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_058216.3(RAD51C):​c.376G>A​(p.Ala126Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00494 in 1,612,814 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A126V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0034 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (30 hom.)
• Consequence: RAD51C NM_058216.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:30
• Conservation: PhyloP100: 5.81
• Publications: 27 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):

• RAD51C-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• breast-ovarian cancer, familial, susceptibility to, 3

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Fanconi anemia complementation group O

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 31 uncertain in NM_058216.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.012307972).
• BP6: Variant 17-58695161-G-A is Benign according to our data. Variant chr17-58695161-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 132721.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00338 (514/152210) while in subpopulation NFE AF = 0.00559 (380/68008). AF 95% confidence interval is 0.00512. There are 3 homozygotes in GnomAd4. There are 238 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD51C	NM_058216.3	MANE Select	c.376G>A	p.Ala126Thr	missense	Exon 2 of 9	NP_478123.1	O43502-1
	RAD51C	NM_002876.4		c.376G>A	p.Ala126Thr	missense	Exon 2 of 2	NP_002867.1	O43502-2
	RAD51C	NR_103872.2		n.418G>A		non_coding_transcript_exon	Exon 2 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD51C	ENST00000337432.9	TSL:1 MANE Select	c.376G>A	p.Ala126Thr	missense	Exon 2 of 9	ENSP00000336701.4	O43502-1
	RAD51C	ENST00000421782.3	TSL:1	c.376G>A	p.Ala126Thr	missense	Exon 2 of 2	ENSP00000391450.2	O43502-2
	RAD51C	ENST00000482007.5	TSL:1	n.376G>A		non_coding_transcript_exon	Exon 2 of 8	ENSP00000433332.1	Q7KZJ0

Frequencies

GnomAD3 genomes AF: 0.00338 AC: 514 AN: 152092 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00559

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00352 AC: 879 AN: 250008 AF XY: 0.00367

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00328

Gnomad ASJ exome AF: 0.00429

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.00541

Gnomad OTH exome AF: 0.00574

GnomAD4 exome AF: 0.00511 AC: 7459 AN: 1460604 Hom.: 30 Cov.: 31 AF XY: 0.00510 AC XY: 3706 AN XY: 726376

African (AFR) AF: 0.000957 AC: 32 AN: 33448

American (AMR) AF: 0.00325 AC: 145 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.00418 AC: 109 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00149 AC: 128 AN: 86080

European-Finnish (FIN) AF: 0.000525 AC: 28 AN: 53322

Middle Eastern (MID) AF: 0.00659 AC: 38 AN: 5762

European-Non Finnish (NFE) AF: 0.00602 AC: 6693 AN: 1111246

Other (OTH) AF: 0.00474 AC: 286 AN: 60356

GnomAD4 genome AF: 0.00338 AC: 514 AN: 152210 Hom.: 3 Cov.: 32 AF XY: 0.00320 AC XY: 238 AN XY: 74436

African (AFR) AF: 0.00113 AC: 47 AN: 41538

American (AMR) AF: 0.00393 AC: 60 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000831 AC: 4 AN: 4816

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00559 AC: 380 AN: 68008

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00558 Hom.: 6

Bravo AF: 0.00343

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00640 AC: 55

ExAC AF: 0.00348 AC: 422

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00654

EpiControl AF: 0.00610

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not provided (8)
-	-	7	not specified (7)
-	-	5	Breast-ovarian cancer, familial, susceptibility to, 3 (5)
-	-	5	Hereditary cancer-predisposing syndrome (5)
-	-	3	Fanconi anemia complementation group O (3)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.016	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.8
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.10
Sift	Benign	0.14	T
Sift4G	Benign	0.27	T
Polyphen		0.066	B
Vest4		0.48
MVP		0.75
MPC		0.31
ClinPred		0.021	T
GERP RS		3.4
PromoterAI		0.0044	Neutral
Varity_R		0.17
gMVP		0.50
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs61758784; hg19: chr17-56772522; COSMIC: COSV104591839;