NM_002878.4(RAD51D):c.493C>T (p.Arg165Trp) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (5 submissions)
Last evaluated:: Dec 27, 2022
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:: RCV000115817.17

Allele description [Variation Report for NM_002878.4(RAD51D):c.493C>T (p.Arg165Trp)]

NM_002878.4(RAD51D):c.493C>T (p.Arg165Trp)

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.493C>T (p.Arg165Trp)

Other names:

p.R165W:CGG>TGG

HGVS:

NC_000017.11:g.35106469G>A
NG_031858.1:g.18401C>T
NM_001142571.2:c.553C>T
NM_002878.4:c.493C>TMANE SELECT
NM_133629.3:c.157C>T
NP_001136043.1:p.Arg185Trp
NP_002869.3:p.Arg165Trp
NP_002869.3:p.Arg165Trp
NP_598332.1:p.Arg53Trp
LRG_516t1:c.493C>T
LRG_516:g.18401C>T
LRG_516p1:p.Arg165Trp
NC_000017.10:g.33433488G>A
NM_001142571.1:c.553C>T
NM_002878.3:c.493C>T
NR_037711.2:n.519C>T
NR_037712.2:n.384C>T
NR_037714.1:n.245C>T
p.R165W

Protein change:

R165W

Links:

dbSNP: rs544654228

NCBI 1000 Genomes Browser:

rs544654228

Molecular consequence:

NM_001142571.2:c.553C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_002878.4:c.493C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_133629.3:c.157C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_037711.2:n.519C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_037712.2:n.384C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_037714.1:n.245C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000214921	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Uncertain significance (Sep 20, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000686463	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 27, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21822267, 29371908, 25741868
SCV000788206	True Health Diagnostics	no assertion criteria provided	Uncertain significance (Jan 5, 2018)	germline	clinical testing
SCV000822181	GeneKor MSA	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 1, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002534824	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Aug 13, 2021)	germline	curation	PubMed (4) [See all records that cite these PMIDs] 29371908, 31159747, 21822267, 26261251 Citation Link

Help

Summary from all submissions

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

Citations

PubMed

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; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Genetic variants of prospectively demonstrated phenocopies in BRCA1/2 kindreds.

Dominguez-Valentin M, Evans DGR, Nakken S, Tubeuf H, Vodak D, Ekstrøm PO, Nissen AM, Morak M, Holinski-Feder E, Martins A, Møller P, Hovig E.

Hered Cancer Clin Pract. 2018;16:4. doi: 10.1186/s13053-018-0086-0.

PubMed [citation]

PMID:: 29371908
PMCID:: PMC5769521

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000214921.6

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

Description

The p.R165W variant (also known as c.493C>T), located in coding exon 6 of the RAD51D gene, results from a C to T substitution at nucleotide position 493. The arginine at codon 165 is replaced by tryptophan, an amino acid with dissimilar properties. In one study, this variant was observed in 0/3429 patients with invasive epithelial ovarian cancer and 1/2772 controls (Song H et al. J. Clin. Oncol. 2015 Sep;33:2901-7). Another case-control study identified this alteration in 0/1822 breast and/or ovarian caner cases, and 1/2120 controls (Loveday C et al. Nat. Genet. 2011 Aug;43(9):879-882). This alteration was also identified in an individual with either breast or ovarian cancer who previously tested negative for a known familial BRCA1/2 mutation (Dominguez-Valentin M et al. Hered Cancer Clin Pract 2018 Jan;16:4). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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

From Color Diagnostics, LLC DBA Color Health, SCV000686463.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant replaces arginine with tryptophan at codon 165 of the RAD51D protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer, together with a pathogenic truncation variant in the ATM gene (PMID: 29371908). This variant has been reported in an unaffected control individual in a breast and ovarian cancer case-control study (PMID: 21822267). This variant has been identified in 13/279074 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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 True Health Diagnostics, SCV000788206.1

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

#	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 GeneKor MSA, SCV000822181.1

#	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	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Sema4, Sema4, SCV002534824.1

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

#	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

Last Updated: Apr 15, 2024

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