NM_000179.3(MSH6):c.866_867delinsAA (p.Gly289Glu) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Aug 1, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000235182.19

Allele description [Variation Report for NM_000179.3(MSH6):c.866_867delinsAA (p.Gly289Glu)]

NM_000179.3(MSH6):c.866_867delinsAA (p.Gly289Glu)

Gene:

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

Variant type:

Indel

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.866_867delinsAA (p.Gly289Glu)

Other names:

p.G289E:GGC>GAA

HGVS:

NC_000002.12:g.47798849_47798850delinsAA
NG_007111.1:g.20703_20704delinsAA
NM_000179.3:c.866_867delinsAAMANE SELECT
NM_001281492.2:c.476_477delinsAA
NM_001281493.2:c.-41_-40delinsAA
NM_001281494.2:c.-41_-40delinsAA
NP_000170.1:p.Gly289Glu
NP_001268421.1:p.Gly159Glu
LRG_219:g.20703_20704delinsAA
NC_000002.11:g.48025988_48025989delinsAA
NM_000179.2:c.866_867delGCinsAA
p.G289E

Protein change:

G159E

Links:

dbSNP: rs267608079

NCBI 1000 Genomes Browser:

rs267608079

Molecular consequence:

NM_001281493.2:c.-41_-40delinsAA - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001281494.2:c.-41_-40delinsAA - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000179.3:c.866_867delinsAA - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.476_477delinsAA - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

Recent activity

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cytochrome oxidase subunit 1, partial (mitochondrion) [Polydrusus tereticollis]
cytochrome oxidase subunit 1, partial (mitochondrion) [Polydrusus tereticollis]
gi|323114578|gb|ADX11924.1|

Protein
Homo sapiens matrix remodeling associated 7 (MXRA7), transcript variant 5, non-c...
Homo sapiens matrix remodeling associated 7 (MXRA7), transcript variant 5, non-coding RNA
gi|1911360034|ref|NR_130927.2|

Nucleotide
GEO Profile Links for Gene (Select 854893) (87)
GEO Profiles
BioProjects for Gene (Select 854893) (2)
BioProject
Full text in PMC (nucleotide) for Gene (Select 854893) (15)
PMC

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000712574	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Nov 15, 2016)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 23621914, 18269114, 16010685, 24033266
SCV000919740	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Aug 1, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 16010685, 20028993, 18269114, 23621914, 26898890, 26333163, 31422818 Citation Link,
SCV002069571	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 15, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000712574

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Nov 15, 2016)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV000919740

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Aug 1, 2024)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link,

SCV002069571

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Sep 15, 2021)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	2	2	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Rapid recognition of aberrant dHPLC elution profiles using the Transgenomic Navigator software.

Colley J, Jones S, Dallosso AR, Maynard JH, Humphreys V, Dolwani S, Sampson JR, Cheadle JP.

Hum Mutat. 2005 Aug;26(2):165.

PubMed [citation]

PMID:: 16010685

See all PubMed Citations (9)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000712574.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (4)

Description

The p.Gly289Glu variant in MSH6 has been classified as a variant of uncertain si gnificance on September 5, 2013 by the ClinGen-approved InSiGHT Expert Panel (Cl inVar SCV000108262.2). It has been reported in 2 individuals with Lynch syndrome associated tumors (Colley 2005, Devlin 2008) and is present in 4/66588 of Europ ean chromosomes in the Exome Aggregation Consortium database (ExAC, http://exac. broadinstitute.org, note that the ExAC database reports this variant as 2 separa te substitutions in cis, c.866G>A [rs267608079] and c.867C>A [rs267608047]). Com putational prediction tools and conservation analysis are limited or unavailable for this variant. In summary, the clinical significance of the p.Gly289Glu vari ant is uncertain.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		2	not provided	2	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919740.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

Variant summary: MSH6 c.866_867delinsAA (p.Gly289Glu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele (comprised of 2 individual constituent variants 2-48025989-C-A and 2-48025988-G-A in cis; GRC37 hg19) was found at a frequency of 8.5e-05 in 282558 control chromosomes, predominantly at a frequency of 0.00019 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.34 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014). c.866_867delinsAA has been reported in the literature in individuals affected with HNPCC, colorectal adenomas, colorectal cancer and breast cancer (example, Colley_2005, Devlin_2008, Baglietto_2010, Caminsky_2016). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch Syndrome. At-least two co-occurrences with pathogenic variants have been observed internally (APC c.4987G>T, p.Glu1663X; CHEK2 c.1555C>T, p.Arg519X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20028993, 26898890, 16010685, 18269114, 31422818, 26333163, 23621914). ClinVar contains an entry for this variant (Variation ID: 89572). Based on the evidence outlined above, the variant was classified as likely benign.

#	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

From Genetic Services Laboratory, University of Chicago, SCV002069571.1

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

Description

DNA sequence analysis of the MSH6 gene demonstrated a deletion and insertion of two base pairs in exon 4, c.866_867delinsAA. This in-frame deletion/insertion results in a missense change, p.Gly289Glu. This sequence change has been identified in individuals with colorectal cancer or suspected Lynch syndrome (PMID: 16010685, 20028993, 18269114). This sequence change has been reported in the gnomAD database with a frequency of 0.02% in the non-Finnish European subpopulation (dbSNPs rs368318845, rs267608047 ). The p.Gly289Glu change affects a poorly conserved amino acid residue located in a domain of the MSH6 protein that is known to be functional. The p.Gly289Glu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Gly289Glu change remains unknown at this time.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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