NM_002878.4(RAD51D):c.412A>C (p.Asn138His) AND Breast-ovarian cancer, familial, susceptibility to, 4

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Feb 22, 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:: RCV000649680.23

Allele description [Variation Report for NM_002878.4(RAD51D):c.412A>C (p.Asn138His)]

NM_002878.4(RAD51D):c.412A>C (p.Asn138His)

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.412A>C (p.Asn138His)

Other names:

p.N138H:AAT>CAT

HGVS:

NC_000017.11:g.35107056T>G
NG_031858.1:g.17814A>C
NM_001142571.2:c.472A>C
NM_002878.4:c.412A>CMANE SELECT
NM_133629.3:c.145-575A>C
NP_001136043.1:p.Asn158His
NP_002869.3:p.Asn138His
NP_002869.3:p.Asn138His
LRG_516t1:c.412A>C
LRG_516:g.17814A>C
LRG_516p1:p.Asn138His
NC_000017.10:g.33434075T>G
NM_002878.3:c.412A>C
NR_037711.2:n.438A>C

Protein change:

N138H

Links:

dbSNP: rs141690729

NCBI 1000 Genomes Browser:

rs141690729

Molecular consequence:

NM_133629.3:c.145-575A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001142571.2:c.472A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_002878.4:c.412A>C - missense variant - [Sequence Ontology: SO:0001583]
NR_037711.2:n.438A>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV000771512	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 26, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 30111881, 31159747, 28492532
SCV001472084	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Uncertain significance (Aug 22, 2019)	germline	clinical testing	Citation Link,
SCV002579319	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 24, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004208088	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 22, 2024)	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	yes	1	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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Contribution of RAD51D germline mutations in breast and ovarian cancer in Greece.

Konstanta I, Fostira F, Apostolou P, Stratikos E, Kalfakakou D, Pampanos A, Kollia P, Papadimitriou C, Konstantopoulou I, Yannoukakos D.

J Hum Genet. 2018 Nov;63(11):1149-1158. doi: 10.1038/s10038-018-0498-8. Epub 2018 Aug 15.

PubMed [citation]

PMID:: 30111881

Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations.

Tsaousis GN, Papadopoulou E, Apessos A, Agiannitopoulos K, Pepe G, Kampouri S, Diamantopoulos N, Floros T, Iosifidou R, Katopodi O, Koumarianou A, Markopoulos C, Papazisis K, Venizelos V, Xanthakis I, Xepapadakis G, Banu E, Eniu DT, Negru S, Stanculeanu DL, Ungureanu A, Ozmen V, et al.

BMC Cancer. 2019 Jun 3;19(1):535. doi: 10.1186/s12885-019-5756-4.

PubMed [citation]

PMID:: 31159747
PMCID:: PMC6547505

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000771512.7

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

Description

This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 138 of the RAD51D protein (p.Asn138His). This variant is present in population databases (rs141690729, gnomAD 0.009%). This missense change has been observed in individual(s) with breast or ovarian cancer (PMID: 30111881, 31159747). ClinVar contains an entry for this variant (Variation ID: 127888). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RAD51D protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been 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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001472084.1

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

Description

The RAD51D c.412A>C; p.Asn138His variant (rs141690729) is reported in the literature in an individual with ovarian cancer (Konstanta 2018), and is reported in ClinVar (Variation ID: 127888). A different variant at this codon (p.Asn138Ser) is also reported in the literature in an individual with ovarian cancer, but was also found in a healthy control individual (Sanchez-Bermudez 2018). The p.Asn138His variant is found in the general population with an overall allele frequency of 0.004% (12/282832 alleles) in the Genome Aggregation Database. The asparagine at codon 138 is moderately conserved, but computational analyses (SIFT: Tolerated, PolyPhen-2: Possibly Damaging) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Konstanta I et al. Contribution of RAD51D germline mutations in breast and ovarian cancer in Greece. J Hum Genet. 2018 Nov;63(11):1149-1158. Sanchez-Bermudez AI et al. Mutational analysis of RAD51C and RAD51D genes in hereditary breast and ovarian cancer families from Murcia (southeastern Spain). Eur J Med Genet. 2018 Jun;61(6):355-361.

#	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 MGZ Medical Genetics Center, SCV002579319.1

#	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 Baylor Genetics, SCV004208088.2

#	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

Last Updated: Oct 20, 2024

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