NM_002878.4(RAD51D):c.412A>C (p.Asn138His) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jan 24, 2023
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:: RCV000572128.15

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]

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
SCV000674693	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jun 24, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30111881, 31159747 Citation Link,
SCV000686451	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 24, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 30111881, 31159747, 33471991, 36011273, 25741868
SCV000822178	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]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000674693

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jun 24, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV000686451

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 24, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV000822178

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]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	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 (5)

Details of each submission

From Ambry Genetics, SCV000674693.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The p.N138H variant (also known as c.412A>C), located in coding exon 5 of the RAD51D gene, results from an A to C substitution at nucleotide position 412. The asparagine at codon 138 is replaced by histidine, an amino acid with similar properties. This alteration has been reported in an ovarian cancer patient from a Greek breast and/or ovarian cancer cohort (Konstanta I et al. J. Hum. Genet., 2018 Nov;63:1149-1158) and in a colorectal cancer patient from a Turkish breast and/or colorectal cancer cohort, listed as a variant of unknown significance (Akcay IM et al. Int J Cancer 2021 01;148(2):285-295). It has also been reported as a variant of unknown significance in 5/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV000686451.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This missense variant replaces asparagine with histidine at codon 138 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 ovarian cancer (PMID: 30111881), in an individual with breast cancer (PMID: 36011273), and in five individuals with a personal or family history of breast and/or ovarian cancer (PMID: 31159747). In a large breast cancer case-control study, this variant was identified in 2/60464 cases and 0/53461 controls (PMID: 33471991 - Leiden Open Variation Database DB-ID RAD51D_000146). This variant has also been identified in 12/282832 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 GeneKor MSA, SCV000822178.1

#	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

Last Updated: Oct 20, 2024

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