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NM_005591.4(MRE11):c.1222dup (p.Thr408fs) AND Hereditary cancer-predisposing syndrome

Clinical significance:Pathogenic (Last evaluated: Oct 12, 2021)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000163829.3

Allele description [Variation Report for NM_005591.4(MRE11):c.1222dup (p.Thr408fs)]

NM_005591.4(MRE11):c.1222dup (p.Thr408fs)

Gene:
MRE11:MRE11 homolog, double strand break repair nuclease [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
11q21
Genomic location:
Preferred name:
NM_005591.4(MRE11):c.1222dup (p.Thr408fs)
HGVS:
  • NC_000011.10:g.94464121dup
  • NG_007261.1:g.34759dup
  • NM_001330347.2:c.1222dup
  • NM_005590.4:c.1222dup
  • NM_005591.4:c.1222dupMANE SELECT
  • NP_001317276.1:p.Thr408fs
  • NP_005581.2:p.Thr408fs
  • NP_005582.1:p.Thr408fs
  • LRG_85:g.34759dup
  • NC_000011.9:g.94197281_94197282insT
  • NC_000011.9:g.94197287dup
  • NM_005591.3:c.1222dupA
  • p.T408NFS*49
Protein change:
T408fs
Links:
dbSNP: rs774440500
NCBI 1000 Genomes Browser:
rs774440500
Molecular consequence:
  • NM_001330347.2:c.1222dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_005590.4:c.1222dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_005591.4:c.1222dup - frameshift variant - [Sequence Ontology: SO:0001589]
Observations:
1

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000214415Ambry Geneticscriteria provided, single submitter
Pathogenic
(Oct 12, 2021)
germlineclinical testing

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Citations

PubMed

Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer.

Pritchard CC, Mateo J, Walsh MF, De Sarkar N, Abida W, Beltran H, Garofalo A, Gulati R, Carreira S, Eeles R, Elemento O, Rubin MA, Robinson D, Lonigro R, Hussain M, Chinnaiyan A, Vinson J, Filipenko J, Garraway L, Taplin ME, AlDubayan S, Han GC, et al.

N Engl J Med. 2016 Aug 4;375(5):443-53. doi: 10.1056/NEJMoa1603144. Epub 2016 Jul 6.

PubMed [citation]
PMID:
27433846
PMCID:
PMC4986616

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

Details of each submission

From Ambry Genetics, SCV000214415.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (2)

Description

The c.1222dupA pathogenic mutation, located in coding exon 10 of the MRE11A gene, results from a duplication of A at nucleotide position 1222, causing a translational frameshift with a predicted alternate stop codon (p.T408Nfs*49). This variant was reported in 1/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant was also identified in 1/692 men with metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis (Pritchard CC et al. N Engl J Med, 2016 Aug;375:443-53), as well as in a proband with pancreatic cancer (Hu C et al. JAMA 2018 06;319(23):2401-2409). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

Last Updated: Jan 21, 2023