rs730881935

Positions:

• chr17-35107104-CT-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_002878.4(RAD51D):​c.363del​(p.Ala122GlnfsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: RAD51D NM_002878.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• Conservation: PhyloP100: 0.352

Genes affected

RAD51D (HGNC:9823): (RAD51 paralog D) 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, which are known to be involved in the homologous recombination and repair of DNA. This protein forms a complex with several other members of the RAD51 family, including RAD51L1, RAD51L2, and XRCC2. The protein complex formed with this protein has been shown to catalyze homologous pairing between single- and double-stranded DNA, and is thought to play a role in the early stage of recombinational repair of DNA. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the downstream ring finger and FYVE-like domain containing 1 (RFFL) gene. [provided by RefSeq, Jan 2011]

RAD51L3-RFFL (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 17-35107104-CT-C is Pathogenic according to our data. Variant chr17-35107104-CT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 182840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD51D	NM_002878.4	c.363del	p.Ala122GlnfsTer14	frameshift_variant	5/10	ENST00000345365.11	NP_002869.3
RAD51L3-RFFL	NR_037714.1	n.233-624del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD51D	ENST00000345365.11	c.363del	p.Ala122GlnfsTer14	frameshift_variant	5/10	1	NM_002878.4	ENSP00000338790	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251416 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135884

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 SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461840 Hom.: 0 Cov.: 32 AF XY: 0.0000275 AC XY: 20 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 4 Pathogenic:6 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 22, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The RAD51D c.423del(p.Ala142GlnfsTer14) variant has been reported in heterozygous state in individuals affected with Breast-Ovarian Cancer (Loveday C et al). This variant has been reported allele frequency 0.001591% in the gnomAD and novel in 1000 genome database. It has been submitted to ClinVar with varying interpretations: Pathogenic/ Likely Pathogenic. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant causes a frameshift starting with codon Alanine 142, changes this amino acid to Glutamine residue, and creates a premature Stop codon at position 14 of the new reading frame, denoted p.Ala142GlnfsTer14. Loss-of-function variants in RAD51D are known to be pathogenic. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 06, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The RAD51D p.Ala122Glnfs*14 variant was identified in 1 of 1922 proband chromosomes (frequency: 0.0005) from individuals or families with breast cancer (Loveday 2011). The variant was also identified in dbSNP (ID: rs730881935) as "With Pathogenic allele", ClinVar (classified as pathogenic by GeneDx, Ambry Genetics, Invitae and one other submitter; and as likely pathogenic by Counsyl). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The c.363del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 122 and leads to a premature stop codon at position 135. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the RAD51D gene are an established mechanism of disease in RAD51D-associated cancers and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -
risk factor, no assertion criteria provided	literature only	OMIM	Aug 07, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2024	This sequence change creates a premature translational stop signal (p.Ala122Glnfs*14) in the RAD51D gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RAD51D are known to be pathogenic (PMID: 21822267). This variant is present in population databases (rs730881935, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with early onset breast cancer (PMID: 21822267). ClinVar contains an entry for this variant (Variation ID: 182840). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 22, 2017	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 02, 2018	This deletion of one nucleotide in RAD51D is denoted c.363delA at the cDNA level and p.Ala122GlnfsX14 (A122QfsX14) at the protein level. The normal sequence, with the base that is deleted in brackets, is TGGC[delA]GCAA. The deletion causes a frameshift, which changes an Alanine to a Glutamine at codon 122, and creates a premature stop codon at position 14 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. RAD51D c.363delA has been seen in a woman with bilateral breast cancer and a family history of ovarian, colon and prostate cancer (Loveday 2011). We consider this variant to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 11, 2018	The variant results in a shift of the reading frame, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 07, 2021	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 14, 2022	The c.363delA pathogenic mutation, located in coding exon 5 of the RAD51D gene, results from a deletion of one nucleotide at nucleotide position 363, causing a translational frameshift with a predicted alternate stop codon (p.A122Qfs*14). This mutation has been reported in multiple individuals with a personal and/or family history of breast and/or ovarian cancer (Loveday C et al. Nat. Genet. 2011 Aug;43:879-82; Susswein LR et al. Genet Med, 2016 08;18:823-32; Yang X et al. J Natl Cancer Inst, 2020 12;112:1242-1250; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 17, 2023	This variant deletes 1 nucleotide in exon 5 of the RAD51D gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 21822267, 26681312, 29470806, 32885271). This variant has been identified in 4/251416 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of RAD51D function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Feb 07, 2022	- -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

Jul 02, 2018

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs730881935; hg19: chr17-33434123;