NM_000179.3(MSH6):c.1144C>T (p.His382Tyr) AND Hereditary cancer-predisposing syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Oct 6, 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.1144C>T (p.His382Tyr)]

NM_000179.3(MSH6):c.1144C>T (p.His382Tyr)

MSH6:mutS homolog 6 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000179.3(MSH6):c.1144C>T (p.His382Tyr)
  • NC_000002.12:g.47799127C>T
  • NG_007111.1:g.20981C>T
  • NM_000179.2:c.1144C>T
  • NM_000179.3:c.1144C>TMANE SELECT
  • NM_001281492.2:c.754C>T
  • NM_001281493.2:c.238C>T
  • NM_001281494.2:c.238C>T
  • NP_000170.1:p.His382Tyr
  • NP_000170.1:p.His382Tyr
  • NP_001268421.1:p.His252Tyr
  • NP_001268422.1:p.His80Tyr
  • NP_001268423.1:p.His80Tyr
  • LRG_219t1:c.1144C>T
  • LRG_219:g.20981C>T
  • LRG_219p1:p.His382Tyr
  • NC_000002.11:g.48026266C>T
  • p.H382Y
Protein change:
dbSNP: rs587779207
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000179.2:c.1144C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000179.3:c.1144C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281492.2:c.754C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281493.2:c.238C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281494.2:c.238C>T - missense variant - [Sequence Ontology: SO:0001583]


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)
SCV000213155Ambry Geneticscriteria provided, single submitter
Likely benign
(Nov 16, 2018)
germlineclinical testing

Citation Link,

SCV000690175Color Health, Inccriteria provided, single submitter
Uncertain significance
(Oct 6, 2020)
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, SCV000213155.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided


Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;In silico models in agreement (benign)

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

From Color Health, Inc, SCV000690175.4

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


This missense variant replaces histidine with tyrosine at codon 382 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 26689913) and an individual in a cohort that was not selected for cancer phenotype (PMID: 31422574). This variant also has been reported in an individual affected with colorectal cancer (LOVD database; https://databases.lovd.nl/shared/individuals/00187081). This variant has been identified in 6/282326 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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

Last Updated: Oct 30, 2021

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