NM_005732.4(RAD50):c.1094G>A (p.Arg365Gln) AND not provided

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Sep 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:: RCV000212907.7

Allele description [Variation Report for NM_005732.4(RAD50):c.1094G>A (p.Arg365Gln)]

NM_005732.4(RAD50):c.1094G>A (p.Arg365Gln)

Gene:

RAD50:RAD50 double strand break repair protein [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q31.1

Genomic location:

Preferred name:

NM_005732.4(RAD50):c.1094G>A (p.Arg365Gln)

Other names:

p.R365Q:CGA>CAA

HGVS:

NC_000005.10:g.132588729G>A
NG_021151.2:g.36753G>A
NM_005732.4:c.1094G>AMANE SELECT
NP_005723.2:p.Arg365Gln
LRG_312t1:c.1094G>A
LRG_312:g.36753G>A
LRG_312p1:p.Arg365Gln
NC_000005.9:g.131924421G>A
NG_021151.1:g.36806G>A
NM_005732.3:c.1094G>A
p.R365Q

Protein change:

R365Q

Links:

dbSNP: rs146370443

NCBI 1000 Genomes Browser:

rs146370443

Molecular consequence:

NM_005732.4:c.1094G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000149835	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (May 17, 2021)	germline	clinical testing	Citation Link,
SCV001552388	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Likely benign	unknown	clinical testing
SCV002009653	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 3, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004219269	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Sep 27, 2022)	unknown	clinical testing	PubMed (11) [See all records that cite these PMIDs] 33471991, 33563768, 32854451, 31159747, 30441849, 30306255, 28550065, 26787654, 26689913, 24894818, 26467025

Help

Summary from all submissions

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

Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.

Breast Cancer Association Consortium., Dorling L, Carvalho S, Allen J, González-Neira A, Luccarini C, Wahlström C, Pooley KA, Parsons MT, Fortuno C, Wang Q, Bolla MK, Dennis J, Keeman R, Alonso MR, Álvarez N, Herraez B, Fernandez V, Núñez-Torres R, Osorio A, Valcich J, Li M, et al.

N Engl J Med. 2021 Feb 4;384(5):428-439. doi: 10.1056/NEJMoa1913948. Epub 2021 Jan 20.

PubMed [citation]

PMID:: 33471991
PMCID:: PMC7611105

See all PubMed Citations (12)

Details of each submission

From GeneDx, SCV000149835.11

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

Description

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast and ovarian cancer (Lu 2015, Fanale 2020); This variant is associated with the following publications: (PMID: 31159747, 32854451, 30441849, 26689913)

#	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 Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001552388.1

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

Description

The RAD50 p.Arg365Gln variant was identified in 5 of 10694 proband chromosomes (frequency: 0.000468) from individuals or families with breast and ovarian cancer and was not identified in 1121 control chromosomes from healthy individuals (Damiola_2014_24894818; Lu_2015_PMID: 26689913). The variant was also identified in dbSNP (ID: rs146370443), ClinVar (conflicting interpretations of pathogenicity: one likely benign submission by Ambry Genetics and four VUS submissions by GeneDx, Invitae, Fulgent Genetics and GeneKor MSA; associated conditions are Nijmegen breakage syndrome-like disorder and Hereditary cancer-predisposing syndrome. The variant was identified in control databases in 122 of 282506 chromosomes at a frequency of 0.000432 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was not identified in the Cosmic and LOVD 3.0 databases. The variant was observed in the following populations: European (non-Finnish) in 79 of 128920 chromosomes (freq: 0.000613), East Asian in 12 of 19952 chromosomes (freq: 0.000601), South Asian in 16 of 30592 chromosomes (freq: 0.000523), Other in 3 of 7210 chromosomes (freq: 0.000416), Latino in 8 of 35398 chromosomes (freq: 0.000226), European (Finnish) in 4 of 25110 chromosomes (freq: 0.000159), while the variant was not observed in the African, and Ashkenazi Jewish populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Arg365 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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

From Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden, SCV002009653.3

#	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	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV004219269.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

The frequency of this variant in the general population, 0.0011 (38/33046 chromosomes in the 'Other non-Finnish European' subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals or families with breast/ovarian cancer (PMIDs: 32854451 (2020), 31159747 (2019), 30306255 (2018), 28550065 (2017), 24894818 (2014)), ovarian cancer alone (PMIDs: 30441849 (2018), 26689913 (2015)), and colorectal cancer (PMID: 33563768 (2022)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.

#	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 13, 2024

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