NM_000179.3(MSH6):c.3563G>A (p.Ser1188Asn) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Mar 1, 2022
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:: RCV000582224.11

Allele description [Variation Report for NM_000179.3(MSH6):c.3563G>A (p.Ser1188Asn)]

NM_000179.3(MSH6):c.3563G>A (p.Ser1188Asn)

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.3563G>A (p.Ser1188Asn)

HGVS:

NC_000002.12:g.47805624G>A
NG_007111.1:g.27478G>A
NG_008397.1:g.105052C>T
NM_000179.3:c.3563G>AMANE SELECT
NM_001281492.2:c.3173G>A
NM_001281493.2:c.2657G>A
NM_001281494.2:c.2657G>A
NP_000170.1:p.Ser1188Asn
NP_000170.1:p.Ser1188Asn
NP_001268421.1:p.Ser1058Asn
NP_001268422.1:p.Ser886Asn
NP_001268423.1:p.Ser886Asn
LRG_219t1:c.3563G>A
LRG_219:g.27478G>A
LRG_219p1:p.Ser1188Asn
NC_000002.11:g.48032763G>A
NM_000179.2:c.3563G>A

Protein change:

S1058N

Links:

dbSNP: rs587779272

NCBI 1000 Genomes Browser:

rs587779272

Molecular consequence:

NM_000179.3:c.3563G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.3173G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.2657G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.2657G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000690376	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 11, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001182118	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Mar 1, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17101317, 21431882, 22495361 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000690376

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 11, 2021)

germline

clinical testing

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

SCV001182118

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Mar 1, 2022)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Pathogenicity of MSH2 missense mutations is typically associated with impaired repair capability of the mutated protein.

Ollila S, Sarantaus L, Kariola R, Chan P, Hampel H, Holinski-Feder E, Macrae F, Kohonen-Corish M, Gerdes AM, Peltomäki P, Mangold E, de la Chapelle A, Greenblatt M, Nyström M.

Gastroenterology. 2006 Nov;131(5):1408-17. Epub 2006 Aug 22.

PubMed [citation]

PMID:: 17101317

See all PubMed Citations (4)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000690376.5

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

Description

This missense variant replaces serine with asparagine at codon 1188 of the MSH6 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold ≥0.7, PMID: 27666373). Functional studies reported this variant as having deficient in vitro DNA repair activity (PMID: 21431882, 31965077). This variant has been reported in individuals suspected of having Lynch syndrome (PMID: 17101317, 21431882, 22495361). This variant has not been identified 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.

#	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 Ambry Genetics, SCV001182118.4

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

Description

The p.S1188N variant (also known as c.3563G>A), located in coding exon 7 of the MSH6 gene, results from a G to A substitution at nucleotide position 3563. The serine at codon 1188 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been previously reported in a family meeting Amsterdam criteria for HNPCC/Lynch syndrome and two affected family members that tested positive for this variant had abnormal, but inconsistent immunohistochemistry (IHC) results. In their colorectal tumors, one individual showed high microsatellite instability (MSI-H), absent MSH6, and reduced MSH2 protein expression while the other showed absent MSH2 with reduced MSH6 protein expression (MSI was not determined). Additionally, the family members who carry the MSH6 p.S1188N alteration also carry a variant of uncertain significance in MSH2 (Okkels H et al. Appl. Immunohistochem. Mol. Morphol. 2012 Oct;20:470-7; Kantelinen J et al. Fam. Cancer. 2011 Sep;10:515-20; Ollila S et al. Gastroenterology. 2006 Nov;131:1408-17). In an in vitro functional assay, MSH6 p.S1188N was reported to be completely deficient in mismatch repair compared to wild type (Kantelinen J et al. Fam. Cancer. 2011 Sep;10:515-20). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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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