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NM_005732.4(RAD50):c.1190A>T (p.His397Leu) AND Hereditary cancer-predisposing syndrome

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Sep 26, 2023
Review status:
criteria provided, conflicting classifications
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:
RCV000167484.15

Allele description [Variation Report for NM_005732.4(RAD50):c.1190A>T (p.His397Leu)]

NM_005732.4(RAD50):c.1190A>T (p.His397Leu)

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.1190A>T (p.His397Leu)
HGVS:
  • NC_000005.10:g.132588825A>T
  • NG_021151.2:g.36849A>T
  • NM_005732.4:c.1190A>TMANE SELECT
  • NP_005723.2:p.His397Leu
  • LRG_312t1:c.1190A>T
  • LRG_312:g.36849A>T
  • LRG_312p1:p.His397Leu
  • NC_000005.9:g.131924517A>T
  • NG_021151.1:g.36902A>T
  • NM_005732.3:c.1190A>T
  • p.H397L
Protein change:
H397L
Links:
dbSNP: rs562153754
NCBI 1000 Genomes Browser:
rs562153754
Molecular consequence:
  • NM_005732.4:c.1190A>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

Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000218341Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely benign
(Sep 1, 2022) 		germlineclinical testing

Citation Link,

SCV000548002Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Sep 26, 2023) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Ambry Genetics, SCV000218341.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000548002.9

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 397 of the RAD50 protein (p.His397Leu). This variant is present in population databases (rs562153754, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with RAD50-related conditions. ClinVar contains an entry for this variant (Variation ID: 187731). 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 RAD50 protein function. 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024