NM_005732.4(RAD50):c.55G>T (p.Asp19Tyr) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 10, 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:: RCV000220877.15

Allele description [Variation Report for NM_005732.4(RAD50):c.55G>T (p.Asp19Tyr)]

NM_005732.4(RAD50):c.55G>T (p.Asp19Tyr)

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.55G>T (p.Asp19Tyr)

HGVS:

NC_000005.10:g.132557379G>T
NG_021151.2:g.5403G>T
NM_005732.4:c.55G>TMANE SELECT
NP_005723.2:p.Asp19Tyr
LRG_312t1:c.55G>T
LRG_312:g.5403G>T
LRG_312p1:p.Asp19Tyr
NC_000005.9:g.131893071G>T
NG_021151.1:g.5456G>T
NM_005732.3:c.55G>T

Protein change:

D19Y

Links:

dbSNP: rs770566177

NCBI 1000 Genomes Browser:

rs770566177

Molecular consequence:

NM_005732.4:c.55G>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000276946	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jul 22, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25452441, 33606809 Citation Link,
SCV000628306	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 10, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25452441, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000276946

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jul 22, 2023)

germline

clinical testing

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

Citation Link,

SCV000628306

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 10, 2023)

germline

clinical testing

PubMed (2)
[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

Germline molecular data in hereditary breast cancer in Brazil: Lessons from a large single-center analysis.

Sandoval RL, Leite ACR, Barbalho DM, Assad DX, Barroso R, Polidorio N, Dos Anjos CH, de Miranda AD, Ferreira ACSM, Fernandes GDS, Achatz MI.

PLoS One. 2021;16(2):e0247363. doi: 10.1371/journal.pone.0247363.

PubMed [citation]

PMID:: 33606809
PMCID:: PMC7895369

Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer.

Couch FJ, Hart SN, Sharma P, Toland AE, Wang X, Miron P, Olson JE, Godwin AK, Pankratz VS, Olswold C, Slettedahl S, Hallberg E, Guidugli L, Davila JI, Beckmann MW, Janni W, Rack B, Ekici AB, Slamon DJ, Konstantopoulou I, Fostira F, Vratimos A, et al.

J Clin Oncol. 2015 Feb 1;33(4):304-11. doi: 10.1200/JCO.2014.57.1414. Epub 2014 Dec 1.

PubMed [citation]

PMID:: 25452441
PMCID:: PMC4302212

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000276946.8

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

Description

The p.D19Y variant (also known as c.55G>T), located in coding exon 1 of the RAD50 gene, results from a G to T substitution at nucleotide position 55. The aspartic acid at codon 19 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration was identified in multiple individuals diagnosed with breast cancer (Couch FJ et al. J Clin Oncol, 2015 Feb;33:304-11; Sandoval RL et al. PLoS One, 2021 Feb;16:e0247363). 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, SCV000628306.9

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

Description

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 19 of the RAD50 protein (p.Asp19Tyr). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer (PMID: 25452441). ClinVar contains an entry for this variant (Variation ID: 232740). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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: Sep 29, 2024

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