15-40698811-AAAGCTTTGGCCCACAA-TATCTTCTT

Variant names:

• chr15-40698811-AAAGCTTTGGCCCACAA-TATCTTCTT
• NM_002875.5:c.53_69delAAAGCTTTGGCCCACAAinsTATCTTCTT

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_002875.5(RAD51):​c.53_69delAAAGCTTTGGCCCACAAinsTATCTTCTT​(p.Glu18ValfsTer44) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAD51 NM_002875.5 frameshift, missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.54
• Publications: 0 publications found

Genes affected

RAD51 (HGNC:9817): (RAD51 recombinase) The protein encoded by this gene is a member of the RAD51 protein 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 the ssDNA-binding protein RPA and RAD52, and it is thought to play roles in homologous pairing and strand transfer of DNA. This protein is also found to interact with BRCA1 and BRCA2, which may be important for the cellular response to DNA damage. BRCA2 is shown to regulate both the intracellular localization and DNA-binding ability of this protein. Loss of these controls following BRCA2 inactivation may be a key event leading to genomic instability and tumorigenesis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2009]

RAD51 Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group R

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• mirror movements 2

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• familial congenital mirror movements

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary breast carcinoma

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 13 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-40698811-AAAGCTTTGGCCCACAA-TATCTTCTT is Pathogenic according to our data. Variant chr15-40698811-AAAGCTTTGGCCCACAA-TATCTTCTT is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2636942.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002875.5. 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
	RAD51	NM_002875.5	MANE Select	c.53_69delAAAGCTTTGGCCCACAAinsTATCTTCTT	p.Glu18ValfsTer44	frameshift missense	Exon 2 of 10	NP_002866.2
	RAD51	NM_001164269.2		c.53_69delAAAGCTTTGGCCCACAAinsTATCTTCTT	p.Glu18ValfsTer44	frameshift missense	Exon 2 of 10	NP_001157741.1	Q06609-4
	RAD51	NM_133487.4		c.53_69delAAAGCTTTGGCCCACAAinsTATCTTCTT	p.Glu18ValfsTer44	frameshift missense	Exon 2 of 10	NP_597994.3	Q06609-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD51	ENST00000267868.8	TSL:1 MANE Select	c.53_69delAAAGCTTTGGCCCACAAinsTATCTTCTT	p.Glu18ValfsTer44	frameshift missense	Exon 2 of 10	ENSP00000267868.3	Q06609-1
	RAD51	ENST00000532743.6	TSL:2	c.53_69delAAAGCTTTGGCCCACAAinsTATCTTCTT	p.Glu18ValfsTer44	frameshift missense	Exon 2 of 10	ENSP00000433924.2	Q06609-1
	RAD51	ENST00000423169.6	TSL:1	c.53_69delAAAGCTTTGGCCCACAAinsTATCTTCTT	p.Glu18ValfsTer44	frameshift missense	Exon 2 of 9	ENSP00000406602.2	Q06609-3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	RAD51-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.5

Splicing

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

Other links and lift over

hg19: chr15-40991009;