dbSNP rs34091239: RAD51:p.Lys285AsnfsTer18 (chr15-40729927-CA-C) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is The variant received 10 classification points (ACMG Germline Pathogenicity v2019). PVS1PM2

The NM_002875.5(RAD51):c.855delA (p.Lys285AsnfsTer18) variant causes a frameshift change. This is a loss-of-function variant that does not trigger NMD. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 8.96). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Consequence

RAD51
NM_002875.5 frameshift

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.96

Publications

1 publications found

Variant links:

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: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
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

RAD51 links:

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new If you want to explore the variant's impact on the transcript NM_002875.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 points.

PVS1

Non-NMD frameshift: ≥4 downstream pathogenic — very strong evidence preserved (PVS1); Frameshift (exon 9 of 10) at amino acid 285 of 339; NMD not predicted. 6 pathogenic variants downstream support preserved loss-of-function impact. A new stop codon is introduced in the shifted frame, truncating the protein to ~301 amino acids (38 amino acids lost).

PM2

Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_002875.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RAD51	NM_002875.5	MANE Select	c.855delA	p.Lys285AsnfsTer18	frameshift	Exon 9 of 10	NP_002866.2
RAD51	NM_001164269.2		c.858delA	p.Lys286AsnfsTer18	frameshift	Exon 9 of 10	NP_001157741.1	Q06609-4
RAD51	NM_133487.4		c.858delA	p.Lys286AsnfsTer18	frameshift	Exon 9 of 10	NP_597994.3	Q06609-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RAD51	ENST00000267868.8	TSL:1 MANE Select	c.855delA	p.Lys285AsnfsTer18	frameshift	Exon 9 of 10	ENSP00000267868.3	Q06609-1
RAD51	ENST00000532743.6	TSL:2	c.855delA	p.Lys285AsnfsTer18	frameshift	Exon 9 of 10	ENSP00000433924.2	Q06609-1
RAD51	ENST00000557850.5	TSL:2	c.564delA	p.Lys188AsnfsTer18	frameshift	Exon 7 of 8	ENSP00000454176.1	Q06609-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

9.0

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over