NM_000179.3(MSH6):c.3619_3620del (p.His1207fs) AND Lynch syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: May 13, 2020
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV004017775.2

Allele description [Variation Report for NM_000179.3(MSH6):c.3619_3620del (p.His1207fs)]

NM_000179.3(MSH6):c.3619_3620del (p.His1207fs)

Gene:

MSH6:mutS homolog 6 [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.3619_3620del (p.His1207fs)

HGVS:

NC_000002.12:g.47805678CA[1]
NC_000002.12:g.47805678_47805679CA[1]
NG_007111.1:g.27532CA[1]
NG_008397.1:g.104995TG[1]
NM_000179.2:c.3619_3620del
NM_000179.3:c.3619_3620delMANE SELECT
NM_001281492.2:c.3229_3230del
NM_001281493.2:c.2713_2714del
NM_001281494.2:c.2713_2714del
NP_000170.1:p.His1207fs
NP_001268421.1:p.His1077fs
NP_001268422.1:p.His905fs
NP_001268423.1:p.His905fs
LRG_219t1:c.3619_3620del
LRG_219:g.27532CA[1]
NC_000002.11:g.48032817CA[1]
NC_000002.11:g.48032817_48032818del
NC_000002.12:g.47805680_47805681delCA
NM_000179.2:c.3619_3620delCA
NM_000179.3:c.3619_3620del

Protein change:

H1077fs

Links:

dbSNP: rs1572741984

NCBI 1000 Genomes Browser:

rs1572741984

Molecular consequence:

NM_000179.3:c.3619_3620del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281492.2:c.3229_3230del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281493.2:c.2713_2714del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281494.2:c.2713_2714del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Lynch syndrome
Identifiers:: MONDO: MONDO:0005835; MedGen: C4552100

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004848354	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (May 13, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27601186, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004848354

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(May 13, 2020)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population.

Lagerstedt-Robinson K, Rohlin A, Aravidis C, Melin B, Nordling M, Stenmark-Askmalm M, Lindblom A, Nilbert M.

Oncol Rep. 2016 Nov;36(5):2823-2835. doi: 10.3892/or.2016.5060. Epub 2016 Sep 1.

PubMed [citation]

PMID:: 27601186

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]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848354.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The p.His1207PhefsX7 variant in MSH6 has been reported in an individual with Lynch syndrome (Lagerstedt-Robinson, 2016) and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1207 and leads to a premature termination codon 7 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the MSH6 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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