NM_000179.2(MSH6):c.4053_4081dup (p.Ter1361Leufs) AND Hereditary cancer-predisposing syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Jun 17, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:

Allele description [Variation Report for NM_000179.2(MSH6):c.4053_4081dup (p.Ter1361Leufs)]

NM_000179.2(MSH6):c.4053_4081dup (p.Ter1361Leufs)

MSH6:mutS homolog 6 [Gene - OMIM - HGNC]
Variant type:
Cytogenetic location:
Genomic location:
Preferred name:
NM_000179.2(MSH6):c.4053_4081dup (p.Ter1361Leufs)
  • NC_000002.12:g.47806830_47806858dup
  • NM_000179.2:c.4053_4081dup
  • LRG_219t1:c.4053_4081dup
  • LRG_219:g.28684_28712dup
  • NC_000002.11:g.48033968_48033969insTAAATTGCTGACTTTGATTAAGGAATTAT
  • NM_000179.2:c.4053_4081dup
  • NM_000179.2:c.4053_4081dup29


Hereditary cancer-predisposing syndrome
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
MONDO: MONDO:0015356; MedGen: C0027672

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000580103Ambry Geneticscriteria provided, single submitter
Likely pathogenic
(Feb 28, 2019)
germlineclinical testing

Citation Link,

SCV001348566Color Health, Inccriteria provided, single submitter
Uncertain significance
(Jun 17, 2019)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing



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]

Details of each submission

From Ambry Genetics, SCV000580103.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided


The c.4053_4081dup29 variant, located in coding exon 10 of the MSH6 gene, results from a duplication of 29 nucleotides at position 4053, causing a translational frameshift with a predicted alternate stop codon (p.*1361Lext*3). Frameshifts are typically deleterious in nature; however, this frameshift occurs at the 3' terminus of MSH6, is not expected to trigger nonsense-mediated mRNA decay, and results in the elongation of the protein by 3 amino acids. The exact functional impact of these inserted amino acids is unknown at this time. In addition, this alteration segregated with colorectal cancer and/or colon polyps in three related individuals whose family history met Amsterdam II criteria for Lynch syndrome (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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

From Color Health, Inc, SCV001348566.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Mar 22, 2021

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