NM_002878.4(RAD51D):c.451C>T (p.Gln151Ter) AND Breast-ovarian cancer, familial, susceptibility to, 4

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Jan 28, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000409676.14

Allele description [Variation Report for NM_002878.4(RAD51D):c.451C>T (p.Gln151Ter)]

NM_002878.4(RAD51D):c.451C>T (p.Gln151Ter)

Genes:

RAD51D:RAD51 paralog D [Gene - OMIM - HGNC]
RAD51L3-RFFL:RAD51L3-RFFL readthrough [Gene]

Variant type:

single nucleotide variant

Cytogenetic location:

17q12

Genomic location:

Preferred name:

NM_002878.4(RAD51D):c.451C>T (p.Gln151Ter)

HGVS:

NC_000017.11:g.35107017G>A
NG_031858.1:g.17853C>T
NM_001142571.2:c.511C>T
NM_002878.4:c.451C>TMANE SELECT
NM_133629.3:c.145-536C>T
NP_001136043.1:p.Gln171Ter
NP_002869.3:p.Gln151Ter
NP_002869.3:p.Gln151Ter
LRG_516t1:c.451C>T
LRG_516:g.17853C>T
LRG_516p1:p.Gln151Ter
NC_000017.10:g.33434036G>A
NM_002878.3:c.451C>T
NM_002878.4:c.451C>T
NR_037711.2:n.477C>T
p.Q151*

Protein change:

Q151*

Links:

dbSNP: rs587781756

NCBI 1000 Genomes Browser:

rs587781756

Molecular consequence:

NM_133629.3:c.145-536C>T - intron variant - [Sequence Ontology: SO:0001627]
NR_037711.2:n.477C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_001142571.2:c.511C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_002878.4:c.451C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Breast-ovarian cancer, familial, susceptibility to, 4
Synonyms:: Breast-ovarian cancer, familial 4
Identifiers:: MONDO: MONDO:0013669; MedGen: C3280345; Orphanet: 145; OMIM: 614291

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000489612	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Likely pathogenic (Nov 2, 2016)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Counsyl Autosomal Dominant Disease Classification criteria (2015), Citation Link,
SCV000651748	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 28, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21822267, 26720728, 28591191, 28492532
SCV000894111	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 31, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001428760	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 11, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004017752	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Pathogenic (Apr 6, 2023)	unknown	clinical testing	Citation Link,
SCV004200445	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 1, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Germline mutations in RAD51D confer susceptibility to ovarian cancer.

Loveday C, Turnbull C, Ramsay E, Hughes D, Ruark E, Frankum JR, Bowden G, Kalmyrzaev B, Warren-Perry M, Snape K, Adlard JW, Barwell J, Berg J, Brady AF, Brewer C, Brice G, Chapman C, Cook J, Davidson R, Donaldson A, Douglas F, Greenhalgh L, et al.

Nat Genet. 2011 Aug 7;43(9):879-882. doi: 10.1038/ng.893.

PubMed [citation]

PMID:: 21822267
PMCID:: PMC4845885

Inherited Mutations in Women With Ovarian Carcinoma.

Norquist BM, Harrell MI, Brady MF, Walsh T, Lee MK, Gulsuner S, Bernards SS, Casadei S, Yi Q, Burger RA, Chan JK, Davidson SA, Mannel RS, DiSilvestro PA, Lankes HA, Ramirez NC, King MC, Swisher EM, Birrer MJ.

JAMA Oncol. 2016 Apr;2(4):482-90. doi: 10.1001/jamaoncol.2015.5495.

PubMed [citation]

PMID:: 26720728
PMCID:: PMC4845939

See all PubMed Citations (5)

PMC

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From Counsyl, SCV000489612.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV000651748.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change creates a premature translational stop signal (p.Gln151*) 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 (rs587781756, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with ovarian cancer (PMID: 26720728, 28591191). This variant is also known as c.511C>T and p.Q171*. ClinVar contains an entry for this variant (Variation ID: 141452). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV000894111.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001428760.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV004017752.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004200445.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 15, 2024

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