NM_005732.4(RAD50):c.3836G>A (p.Arg1279His) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 26, 2025
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:: RCV000129203.19

Allele description [Variation Report for NM_005732.4(RAD50):c.3836G>A (p.Arg1279His)]

NM_005732.4(RAD50):c.3836G>A (p.Arg1279His)

Genes:

RAD50:RAD50 double strand break repair protein [Gene - OMIM - HGNC]
TH2LCRR:T helper type 2 locus control region associated RNA [Gene - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q31.1

Genomic location:

Preferred name:

NM_005732.4(RAD50):c.3836G>A (p.Arg1279His)

HGVS:

NC_000005.10:g.132642261G>A
NG_021151.2:g.90285G>A
NG_042308.1:g.13099G>A
NM_005732.4:c.3836G>AMANE SELECT
NP_005723.2:p.Arg1279His
LRG_312t1:c.3836G>A
LRG_312:g.90285G>A
LRG_312p1:p.Arg1279His
NC_000005.9:g.131977953G>A
NG_021151.1:g.90338G>A
NM_005732.3:c.3836G>A
NR_132125.1:n.126C>T
p.R1279H

Protein change:

R1279H

Links:

dbSNP: rs375710541

NCBI 1000 Genomes Browser:

rs375710541

Molecular consequence:

NM_005732.4:c.3836G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_132125.1:n.126C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Hereditary neoplastic syndrome; 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
SCV000183947	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Sep 29, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24894818, 27783279, 36035419 Citation Link,
SCV000289069	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 26, 2025)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24894818, 27783279, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000183947

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Sep 29, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV000289069

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 26, 2025)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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

Citations

PubMed

Multi-gene panel testing increases germline predisposing mutations' detection in a cohort of breast/ovarian cancer patients from Southern Italy.

Nunziato M, Di Maggio F, Pensabene M, Esposito MV, Starnone F, De Angelis C, Calabrese A, D'Aiuto M, Botti G, De Placido S, D'Argenio V, Salvatore F.

Front Med (Lausanne). 2022;9:894358. doi: 10.3389/fmed.2022.894358.

PubMed [citation]

PMID:: 36035419
PMCID:: PMC9403188

Rare key functional domain missense substitutions in MRE11A, RAD50, and NBN contribute to breast cancer susceptibility: results from a Breast Cancer Family Registry case-control mutation-screening study.

Damiola F, Pertesi M, Oliver J, Le Calvez-Kelm F, Voegele C, Young EL, Robinot N, Forey N, Durand G, Vallée MP, Tao K, Roane TC, Williams GJ, Hopper JL, Southey MC, Andrulis IL, John EM, Goldgar DE, Lesueur F, Tavtigian SV.

Breast Cancer Res. 2014 Jun 3;16(3):R58. doi: 10.1186/bcr3669.

PubMed [citation]

PMID:: 24894818
PMCID:: PMC4229874

See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000183947.8

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

Description

The p.R1279H variant (also known as c.3836G>A), located in coding exon 25 of the RAD50 gene, results from a G to A substitution at nucleotide position 3836. The arginine at codon 1279 is replaced by histidine, an amino acid with highly similar properties. This alteration was identified in multiple individuals diagnosed with breast and/or ovarian cancer (Damiola F et al. Breast Cancer Res, 2014 Jun;16:R58; Kim H et al. Breast Cancer Res Treat, 2017 01;161:95-102; Nunziato M et al. Front Med (Lausanne), 2022 Aug;9:894358). This amino acid position is highly 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000289069.12

#	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 arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1279 of the RAD50 protein (p.Arg1279His). This variant is present in population databases (rs375710541, gnomAD 0.01%). This missense change has been observed in individual(s) with a personal and/or family history of breast cancer (PMID: 24894818, 27783279). ClinVar contains an entry for this variant (Variation ID: 140931). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt RAD50 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

Last Updated: May 16, 2025

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