17-58720767-A-G

Variant names:

• chr17-58720767-A-G
• rs28363317
• NM_058216.3:c.859A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_058216.3(RAD51C):​c.859A>G​(p.Thr287Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0088 in 1,612,322 control chromosomes in the GnomAD database, including 80 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. T287P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0063 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0091 (77 hom.)
• Consequence: RAD51C NM_058216.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:34
• Conservation: PhyloP100: 4.88
• Publications: 41 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012393534).
• BP6: Variant 17-58720767-A-G is Benign according to our data. Variant chr17-58720767-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 132702.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 = 0.0063 (960/152314) while in subpopulation NFE AF = 0.0103 (699/68024). AF 95% confidence interval is 0.00964. There are 3 homozygotes in GnomAd4. There are 421 alleles in the male GnomAd4 subpopulation. Median coverage is 31. 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.859A>G	p.Thr287Ala	missense	Exon 6 of 9	NP_478123.1	O43502-1
	RAD51C	NR_103872.2		n.734A>G		non_coding_transcript_exon	Exon 5 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD51C	ENST00000337432.9	TSL:1 MANE Select	c.859A>G	p.Thr287Ala	missense	Exon 6 of 9	ENSP00000336701.4	O43502-1
	RAD51C	ENST00000482007.5	TSL:1	n.*287A>G		non_coding_transcript_exon	Exon 5 of 8	ENSP00000433332.1	Q7KZJ0
	RAD51C	ENST00000482007.5	TSL:1	n.*287A>G		3_prime_UTR	Exon 5 of 8	ENSP00000433332.1	Q7KZJ0

Frequencies

GnomAD3 genomes AF: 0.00631 AC: 961 AN: 152196 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00896

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0103

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.00560 AC: 1407 AN: 251152 AF XY: 0.00548

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.00590

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000651

Gnomad NFE exome AF: 0.00961

Gnomad OTH exome AF: 0.00815

GnomAD4 exome AF: 0.00907 AC: 13236 AN: 1460008 Hom.: 77 Cov.: 30 AF XY: 0.00876 AC XY: 6361 AN XY: 726460

African (AFR) AF: 0.00156 AC: 52 AN: 33434

American (AMR) AF: 0.00651 AC: 291 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.000728 AC: 19 AN: 26112

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39652

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86228

European-Finnish (FIN) AF: 0.000790 AC: 42 AN: 53198

Middle Eastern (MID) AF: 0.00142 AC: 8 AN: 5640

European-Non Finnish (NFE) AF: 0.0111 AC: 12331 AN: 1110726

Other (OTH) AF: 0.00793 AC: 478 AN: 60314

GnomAD4 genome AF: 0.00630 AC: 960 AN: 152314 Hom.: 3 Cov.: 31 AF XY: 0.00565 AC XY: 421 AN XY: 74482

African (AFR) AF: 0.00192 AC: 80 AN: 41576

American (AMR) AF: 0.00895 AC: 137 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10622

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0103 AC: 699 AN: 68024

Other (OTH) AF: 0.0128 AC: 27 AN: 2110

Alfa AF: 0.00869 Hom.: 25

Bravo AF: 0.00695

TwinsUK AF: 0.0113 AC: 42

ALSPAC AF: 0.00986 AC: 38

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0102 AC: 88

ExAC AF: 0.00542 AC: 658

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00889

EpiControl AF: 0.00996

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not provided (10)
-	-	7	not specified (7)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	3	Breast-ovarian cancer, familial, susceptibility to, 3 (3)
-	-	3	Fanconi anemia complementation group O (3)
-	-	2	Hereditary breast ovarian cancer syndrome (2)
-	-	1	Breast and Ovarian Cancer Susceptibility (1)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Fanconi anemia (1)
-	-	1	Malignant tumor of breast (1)
-	-	1	RAD51C-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.045	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.046	D
Polyphen		0.99	D
Vest4		0.61
MVP		0.77
MPC		0.74
ClinPred		0.044	T
GERP RS		5.1
Varity_R		0.77
gMVP		0.81
Mutation Taster		=85/15	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: rs28363317; hg19: chr17-56798128;