17-58709943-G-A

Variant names:

• chr17-58709943-G-A
• rs147241704
• NM_058216.3:c.790G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_058216.3(RAD51C):​c.790G>A​(p.Gly264Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00314 in 1,613,062 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G264V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0033 (16 hom.)
• Consequence: RAD51C NM_058216.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:26 O:1
• Conservation: PhyloP100: 7.47
• Publications: 38 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010389477).
• BP6: Variant 17-58709943-G-A is Benign according to our data. Variant chr17-58709943-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 128211.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.002 (305/152166) while in subpopulation NFE AF = 0.00335 (228/68008). AF 95% confidence interval is 0.003. There are 1 homozygotes in GnomAd4. There are 133 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 16 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD51C	NM_058216.3	MANE Select	c.790G>A	p.Gly264Ser	missense	Exon 5 of 9	NP_478123.1
	RAD51C	NR_103872.2		n.665G>A		non_coding_transcript_exon	Exon 4 of 8

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD51C	ENST00000337432.9	TSL:1 MANE Select	c.790G>A	p.Gly264Ser	missense	Exon 5 of 9	ENSP00000336701.4
	RAD51C	ENST00000482007.5	TSL:1	n.*218G>A		non_coding_transcript_exon	Exon 4 of 8	ENSP00000433332.1
	RAD51C	ENST00000482007.5	TSL:1	n.*218G>A		3_prime_UTR	Exon 4 of 8	ENSP00000433332.1

Frequencies

GnomAD3 genomes AF: 0.00201 AC: 305 AN: 152048 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00335

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00175 AC: 439 AN: 251430 AF XY: 0.00173

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000785

Gnomad NFE exome AF: 0.00346

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00326 AC: 4758 AN: 1460896 Hom.: 16 Cov.: 30 AF XY: 0.00307 AC XY: 2232 AN XY: 726814

African (AFR) AF: 0.000598 AC: 20 AN: 33466

American (AMR) AF: 0.0000447 AC: 2 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86242

European-Finnish (FIN) AF: 0.000805 AC: 43 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00411 AC: 4562 AN: 1111144

Other (OTH) AF: 0.00179 AC: 108 AN: 60348

GnomAD4 genome AF: 0.00200 AC: 305 AN: 152166 Hom.: 1 Cov.: 30 AF XY: 0.00179 AC XY: 133 AN XY: 74386

African (AFR) AF: 0.000674 AC: 28 AN: 41514

American (AMR) AF: 0.000328 AC: 5 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.000566 AC: 6 AN: 10592

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

European-Non Finnish (NFE) AF: 0.00335 AC: 228 AN: 68008

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.00319 Hom.: 1

Bravo AF: 0.00215

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00185 AC: 225

EpiCase AF: 0.00300

EpiControl AF: 0.00290

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	10	not provided (11)
-	2	5	Hereditary cancer-predisposing syndrome (7)
-	1	2	Breast-ovarian cancer, familial, susceptibility to, 3 (3)
-	-	3	not specified (3)
-	1	1	Fanconi anemia complementation group O (2)
-	1	1	Hereditary breast ovarian cancer syndrome (2)
-	-	1	Breast and/or ovarian cancer (1)
-	1	-	Familial cancer of breast (1)
-	-	1	Fanconi anemia complementation group O;C3150659:Breast-ovarian cancer, familial, susceptibility to, 3 (1)
-	-	1	Malignant tumor of breast (1)
-	-	1	RAD51C-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.3	L
PhyloP100		7.5
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.20
Sift	Uncertain	0.014	D
Sift4G	Benign	0.45	T
Polyphen		0.057	B
Vest4		0.64
MVP		0.69
MPC		0.25
ClinPred		0.028	T
GERP RS		6.0
PromoterAI		-0.063	Neutral
Varity_R		0.58
gMVP		0.52
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs147241704; hg19: chr17-56787304; COSMIC: COSV104641800;