NM_000179.3(MSH6):c.3557G>A (p.Gly1186Asp) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: May 18, 2024
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:: RCV000129855.14

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]

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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Zfp36l1 protein [Mus musculus]
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000184672	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (May 18, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001354496	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 10, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 33471991, 25741868
SCV002528047	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Nov 2, 2021)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 31422818, 33471991 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000184672

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(May 18, 2024)

germline

clinical testing

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

Citation Link,

SCV001354496

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 10, 2023)

germline

clinical testing

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

SCV002528047

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Nov 2, 2021)

germline

curation

PubMed (2)
[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, curation

Citations

PubMed

Family History of Colorectal or Esophageal Cancer in Barrett's Esophagus and Potentially Explanatory Genetic Variants.

Rubenstein JH, Tavakkoli A, Koeppe E, Ulintz P, Inadomi JM, Morgenstern H, Appelman H, Scheiman JM, Schoenfeld P, Metko V, Stoffel EM.

Clin Transl Gastroenterol. 2020 Apr;11(4):e00151. doi: 10.14309/ctg.0000000000000151.

PubMed [citation]

PMID:: 32251017
PMCID:: PMC7263651

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

See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000184672.10

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

Description

The p.G1186D variant (also known as c.3557G>A), located in coding exon 7 of the MSH6 gene, results from a G to A substitution at nucleotide position 3557. The glycine at codon 1186 is replaced by aspartic acid, an amino acid with similar properties. This change occurs in the first base pair of coding exon 7. RNA studies have demonstrated that this alteration does not result in abnormal splicing in the set of samples tested (Ambry internal data). This variant was identified in a male proband with Barrett’s esophagus who had a family history of esophageal cancer in a first-degree relative (Rubenstein JH et al. Clin Transl Gastroenterol, 2020 Apr;11:e00151). 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

From Color Diagnostics, LLC DBA Color Health, SCV001354496.3

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

Description

This missense variant replaces glycine with aspartic acid at codon 1186 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with Lynch syndrome or colorectal cancer cancer in the literature. In a large breast cancer case-control study, This variant has been observed in 2/60466 cases and 0/53461 unaffected controls (PMID: 33471991). This variant has been identified in 5/249444 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.

#	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 Sema4, Sema4, SCV002528047.1

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

#	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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