NM_000179.3(MSH6):c.3557G>A (p.Gly1186Asp) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Aug 4, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000485699.7

Allele description [Variation Report for NM_000179.3(MSH6):c.3557G>A (p.Gly1186Asp)]

NM_000179.3(MSH6):c.3557G>A (p.Gly1186Asp)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.3557G>A (p.Gly1186Asp)

HGVS:

NC_000002.12:g.47805618G>A
NG_007111.1:g.27472G>A
NG_008397.1:g.105058C>T
NM_000179.3:c.3557G>AMANE SELECT
NM_001281492.2:c.3167G>A
NM_001281493.2:c.2651G>A
NM_001281494.2:c.2651G>A
NP_000170.1:p.Gly1186Asp
NP_000170.1:p.Gly1186Asp
NP_001268421.1:p.Gly1056Asp
NP_001268422.1:p.Gly884Asp
NP_001268423.1:p.Gly884Asp
LRG_219t1:c.3557G>A
LRG_219:g.27472G>A
LRG_219p1:p.Gly1186Asp
NC_000002.11:g.48032757G>A
NM_000179.2:c.3557G>A
p.G1186D

Protein change:

G1056D

Links:

dbSNP: rs587781690

NCBI 1000 Genomes Browser:

rs587781690

Molecular consequence:

NM_000179.3:c.3557G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.3167G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.2651G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.2651G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Mus musculus SH3-binding kinase 1, mRNA (cDNA clone MGC:28537 IMAGE:4194152), co...
Mus musculus SH3-binding kinase 1, mRNA (cDNA clone MGC:28537 IMAGE:4194152), complete cds
gi|21594543|gb|BC031759.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000712797	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Jan 25, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004037859	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Aug 4, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 31422818, 33471991, 32251017 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000712797

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Jan 25, 2017)

germline

clinical testing

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

SCV004037859

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Aug 4, 2023)

germline

clinical testing

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	1	1	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	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

Rates of Actionable Genetic Findings in Individuals with Colorectal Cancer or Polyps Ascertained from a Community Medical Setting.

Gordon AS, Rosenthal EA, Carrell DS, Amendola LM, Dorschner MO, Scrol A, Stanaway IB, DeVange S, Ralston JD, Zouk H, Rehm HL, Larson E, Crosslin DR, Leppig KA, Jarvik GP.

Am J Hum Genet. 2019 Sep 5;105(3):526-533. doi: 10.1016/j.ajhg.2019.07.012. Epub 2019 Aug 15.

PubMed [citation]

PMID:: 31422818
PMCID:: PMC6731361

See all PubMed Citations (4)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000712797.1

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

Description

The p.Gly1186Asp variant in MSH6 has not been previously reported in individuals with Lynch syndrome but has been identified in 3/66564 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs587781690). This variant is located in the first base of the exon, which is part of the 3? splice region. Splicing prediction tools do not suggest altered s plicing and computational prediction tools and conservation analysis suggest tha t the p.Gly1186Asp variant may impact the protein, though this information is no t predictive enough to determine pathogenicity. In summary, the clinical signifi cance of the p.Gly1186Asp variant 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		1	not provided	1	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004037859.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: MSH6 c.3557G>A (p.Gly1186Asp) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain (IPR000432) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Two computational tools predict no significant impact on normal splicing and 2 predict the variant weakens the canonical 3' acceptor splice site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2e-05 in 249444 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3557G>A has been reported in the literature in individuals affected with Colorectal Cancer (Gordon_2019), Esophageal Cancer (Rubenstein_2020) and Breast Cancer (Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. 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: 31422818, 32251017, 33471991). Eight ClinVar submitters have assessed the variant since 2014, and all submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

#	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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