chr17-58695189-G-A

Variant names:

• chr17-58695189-G-A
• rs767796996
• ENST00000421782.3:c.404G>A

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1_Strong PS3 PM2 PP3_Moderate PP5_Very_Strong

The NM_002876.4(RAD51C):​c.404G>A​(p.Trp135*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000278700: RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). RNA analyses on another similar variant at the same nucleotide position, p.C135S (c.404G>C), has shown the introduction of a new premature stop codon into the coding sequence (Neidhardt G et al. Eur. J. Cancer Prev. 2017 Mar;26:165-169, Ambry internal data).; SCV000909441: Functional studies have shown that this variant has a deleterious impact on homologous recombination, protein stability, interactions with RAD51 paralogs (RAD51D, RAD51B, XRCC3), protein complex formation, drug response (olaparib and cisplatin), and RAD51 foci formation (PMID:22451500, 36099300, 37253112, 37843130).; SCV000550186: Experimental studies have shown that this missense change affects RAD51C function (PMID:22451500).; SCV000920120: An in vitro study, examining the effect of this variant at the protein level, using an (intronless) cDNA construct, demonstrated an approximately 50% reduction in RAD51C foci formation (a surrogate measure of homology-directed repair) (Osorio_2012).; SCV001812635: Published functional studies demonstrate a damaging effect: unable to restore RAD51 foci formation (Osorio et al., 2012);; SCV004931388: mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID:33011440].".

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RAD51C NM_002876.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 8.75
• Publications: 21 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: Pathogenic. The variant received 20 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 8 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000278700: RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). RNA analyses on another similar variant at the same nucleotide position, p.C135S (c.404G>C), has shown the introduction of a new premature stop codon into the coding sequence (Neidhardt G et al. Eur. J. Cancer Prev. 2017 Mar;26:165-169, Ambry internal data).; SCV000909441: Functional studies have shown that this variant has a deleterious impact on homologous recombination, protein stability, interactions with RAD51 paralogs (RAD51D, RAD51B, XRCC3), protein complex formation, drug response (olaparib and cisplatin), and RAD51 foci formation (PMID: 22451500, 36099300, 37253112, 37843130).; SCV000550186: Experimental studies have shown that this missense change affects RAD51C function (PMID: 22451500).; SCV000920120: An in vitro study, examining the effect of this variant at the protein level, using an (intronless) cDNA construct, demonstrated an approximately 50% reduction in RAD51C foci formation (a surrogate measure of homology-directed repair) (Osorio_2012).; SCV001812635: Published functional studies demonstrate a damaging effect: unable to restore RAD51 foci formation (Osorio et al., 2012);; SCV004931388: mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 33011440].
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-58695189-G-A is Pathogenic according to our data. Variant chr17-58695189-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 234175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002876.4. 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.404G>A	p.Cys135Tyr	missense splice_region	Exon 2 of 9	NP_478123.1	O43502-1
	RAD51C	NM_002876.4		c.404G>A	p.Trp135*	stop_gained	Exon 2 of 2	NP_002867.1	O43502-2
	RAD51C	NR_103872.2		n.446G>A		splice_region non_coding_transcript_exon	Exon 2 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD51C	ENST00000421782.3	TSL:1	c.404G>A	p.Trp135*	stop_gained	Exon 2 of 2	ENSP00000391450.2	O43502-2
	RAD51C	ENST00000337432.9	TSL:1 MANE Select	c.404G>A	p.Cys135Tyr	missense splice_region	Exon 2 of 9	ENSP00000336701.4	O43502-1
	RAD51C	ENST00000482007.5	TSL:1	n.404G>A		splice_region non_coding_transcript_exon	Exon 2 of 8	ENSP00000433332.1	Q7KZJ0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000405 AC: 1 AN: 246764 AF XY: 0.00000748

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000899

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457398 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 724394

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33338

American (AMR) AF: 0.00 AC: 0 AN: 44318

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26038

East Asian (EAS) AF: 0.00 AC: 0 AN: 39620

South Asian (SAS) AF: 0.00 AC: 0 AN: 85840

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52850

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109408

Other (OTH) AF: 0.00 AC: 0 AN: 60234

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0448430), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Breast-ovarian cancer, familial, susceptibility to, 3 (4)
2	-	-	Hereditary breast ovarian cancer syndrome (2)
2	-	-	Hereditary cancer-predisposing syndrome (2)
2	-	-	not provided (2)
1	-	-	Fanconi anemia complementation group O (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	35
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.42	T
MutationAssessor	Pathogenic	4.0	H
PhyloP100		8.8
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.026	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.73		Gain of phosphorylation at C135 (P = 0.0652)
MVP		0.86
MPC		1.1
ClinPred		1.0	D
GERP RS		5.1
PromoterAI		-0.0083	Neutral
Varity_R		0.95
gMVP		0.91
Mutation Taster		=29/171	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
SpliceAI score (max)		0.85		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.24		Position offset: -22
DS_DL_spliceai		0.85		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs767796996; hg19: chr17-56772550;