NM_000179.3(MSH6):c.3482CTG[1] (p.Ala1162del) AND Hereditary cancer-predisposing syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Apr 21, 2020)

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_000179.3(MSH6):c.3482CTG[1] (p.Ala1162del)]

NM_000179.3(MSH6):c.3482CTG[1] (p.Ala1162del)

MSH6:mutS homolog 6 [Gene - OMIM - HGNC]
Variant type:
Cytogenetic location:
Genomic location:
Preferred name:
NM_000179.3(MSH6):c.3482CTG[1] (p.Ala1162del)
  • NC_000002.12:g.47804953CTG[1]
  • NG_007111.1:g.26807CTG[1]
  • NG_008397.1:g.105718CAG[1]
  • NM_000179.3:c.3482CTG[1]MANE SELECT
  • NM_001281492.2:c.3092CTG[1]
  • NM_001281493.2:c.2576CTG[1]
  • NM_001281494.2:c.2576CTG[1]
  • NP_000170.1:p.Ala1162del
  • NP_001268421.1:p.Ala1032del
  • NP_001268422.1:p.Ala860del
  • NP_001268423.1:p.Ala860del
  • LRG_219:g.26807CTG[1]
  • NC_000002.11:g.48032092CTG[1]
  • NM_000179.2:c.3485_3487delCTG
  • p.A1162del
Protein change:
dbSNP: rs63751427
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000179.3:c.3482CTG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
  • NM_001281492.2:c.3092CTG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
  • NM_001281493.2:c.2576CTG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
  • NM_001281494.2:c.2576CTG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]


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)
SCV000172773Ambry Geneticscriteria provided, single submitter
Likely pathogenic
(Apr 21, 2020)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV000908422Color Health, Inccriteria provided, single submitter
Uncertain significance
(Jul 14, 2018)
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



Prevalence of defective DNA mismatch repair and MSH6 mutation in an unselected series of endometrial cancers.

Goodfellow PJ, Buttin BM, Herzog TJ, Rader JS, Gibb RK, Swisher E, Look K, Walls KC, Fan MY, Mutch DG.

Proc Natl Acad Sci U S A. 2003 May 13;100(10):5908-13. Epub 2003 May 5.

PubMed [citation]

Structure of the human MutSalpha DNA lesion recognition complex.

Warren JJ, Pohlhaus TJ, Changela A, Iyer RR, Modrich PL, Beese LS.

Mol Cell. 2007 May 25;26(4):579-92.

PubMed [citation]
See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000172773.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (3)


The c.3485_3487delCTG variant (also known as p.A1162del) is located in coding exon 6 of the MSH6 gene. This alteration results from the deletion of 3 nucleotides at positions 3485 to 3487, causing the deletion of a highly-conserved alanine residue at codon 1162. The amino acid resides in a well-defined functional domain and is adjacent to a helix that contains the MSH6 ATP binding p-loop (Warren JJ et al. Mol. Cell 2007 May;26(4):579-92). This alteration has been identified in three individuals with endometrial cancer and ages at diagnosis ranged from 45y to 54y. One of the individuals was also diagnosed with rectal cancer at the age of 60y. Tumor results for two of the individuals revealed loss of MSH6 protein expression on immunohistochemistry while the third individual had a family history that met Amsterdam criteria (Ambry internal data). The alteration was also reported in a patient with endometrial cancer and rectal cancer diagnosed at the ages of 53y and 61y, respectively. Furthermore, tumor results from the endometrial cancer revealed microsatellite instability (MSI-H) (Goodfellow PJ et al. Proc. Natl. Acad. Sci. U.S.A. 2003 May;100(10: 5908-13). In addition, this alteration is predicted to be deleterious by PROVEAN in silico analysis (Choi Y et al. PLoS ONE 2012 ; 7(10):e46688). 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, SCV000908422.1

#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: May 28, 2021

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