rs753862052

Positions:

• chr17-35107439-T-TTA

Variant summary

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

The NM_002878.4(RAD51D):​c.270_271dupTA​(p.Lys91fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,547,768 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: 𝑓 0.000013 (0 hom., 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:15
• Conservation: PhyloP100: 2.30

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]

ENSG00000267618 (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 17-35107439-T-TTA is Pathogenic according to our data. Variant chr17-35107439-T-TTA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 239394.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.270_271dupTA	p.Lys91fs	frameshift_variant	4/10	ENST00000345365.11	NP_002869.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD51D	ENST00000345365.11	c.270_271dupTA	p.Lys91fs	frameshift_variant	4/10	1	NM_002878.4	ENSP00000338790.6
ENSG00000267618	ENST00000593039.5	c.4-960_4-959dupTA		intron_variant		2		ENSP00000466834.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152064 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000557 AC: 14 AN: 251448 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000761

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000172 AC: 24 AN: 1395586 Hom.: 0 Cov.: 31 AF XY: 0.0000158 AC XY: 11 AN XY: 697318

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000609

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152182 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74412

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000119 Hom.: 0

Bravo AF: 0.0000416

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 4 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change creates a premature translational stop signal (p.Lys91Ilefs*13) 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 (rs753862052, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with male breast cancer and ovarian and breast cancer (PMID: 21822267, 28008555). ClinVar contains an entry for this variant (Variation ID: 239394). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 10, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 02, 2017	- -
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, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PVS1+PM2_Supporting+PS4_Moderate -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 2023	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Also known as c.271_272insTA, c.330_331dupTA; This variant is associated with the following publications: (PMID: 23372765, 28495237, 21822267, 28008555, 28724667, 26296696, 29020732, 29566657, 29348823, 28522256, 30165555, 32068069, 34917121, 32107557, 30875412, 33151324, 30982232, 32566746, 32318955, 26681312, 35273153, 28888541, 36225625, 35641994, 32980694) -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	May 18, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 22, 2022	The c.270_271dupTA pathogenic mutation, located in coding exon 4 of the RAD51D gene, results from a duplication of TA at nucleotide position 270, causing a translational frameshift with a predicted alternate stop codon (p.K91Ifs*13). This mutation has been detected in multiple ovarian cancer patients as well as male and female breast cancer patients (Loveday C et al. Nat. Genet. 2011 Sep;43:879-82; Frey MK et al. Gynecol. Oncol. 2015 Nov;139:211-5; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Pritzlaff M et al. Breast Cancer Res. Treat. 2017 Feb;161:575-586; Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119; Hirasawa A et al. Oncotarget. 2017 Nov;8:112258-112267; Wang YA et al. BMC Cancer. 2018 Mar;18:315; Eoh KJ et al. Cancer Res Treat. 2018 Jul;50:917-925). 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	Apr 03, 2023	This variant inserts 2 nucleotides in exon 4 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 multiple individuals affected with breast and/or ovarian cancer (PMID: 21822267, 28008555, 29020732, 29348823, 32068069, 32359370, 35186721, 36544182). This variant also has been detected in a two breast cancer case-control studies in 15/60463 cases and 5/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID RAD51D_000038) and in 3/831 cases and 2/839 unaffected individuals (PMID: 32318955). This variant has been identified in 14/251448 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. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 21, 2021	Variant summary: RAD51D c.270_271dupTA (p.Lys91IlefsX13) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 6.3e-05 in 253126 control chromosomes, predominantly at a frequency of 0.00076 within the East Asian subpopulation in the gnomAD database. c.270_271dupTA has been reported in the literature in multiple individuals affected with Breast and Ovarian Cancer (example: Loveday_2011, Sun_2017, Zeng_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. In addition, a recent large case-control study evaluating breast cancer cases and controls and a large scale meta-analyses evaluating ovarian cancer cases and controls found a moderate risk association of RAD51D truncating variants with familial breast cancer (overall odds ratio (OR) =1.80, 95% Cis: 1.112.93, p=0.018) as well as with ovarian cancer (overall OR = 6.94, 95% CI: 5.109.44; p< 0.0001) (Dorling_2021, Suszynska_2020). Six other ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	research	Cancer Genomics Group, Japanese Foundation For Cancer Research	May 01, 2019	- -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Ovarian neoplasm Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

China-NCC-Department of Gynecologic Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs753862052; hg19: chr17-33434458;