NM_000179.3(MSH6):c.2235T>G (p.Ile745Met) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 12, 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:: RCV001014897.6

Allele description [Variation Report for NM_000179.3(MSH6):c.2235T>G (p.Ile745Met)]

NM_000179.3(MSH6):c.2235T>G (p.Ile745Met)

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.2235T>G (p.Ile745Met)

HGVS:

NC_000002.12:g.47800218T>G
NG_007111.1:g.22072T>G
NM_000179.3:c.2235T>GMANE SELECT
NM_001281492.2:c.1845T>G
NM_001281493.2:c.1329T>G
NM_001281494.2:c.1329T>G
NP_000170.1:p.Ile745Met
NP_000170.1:p.Ile745Met
NP_001268421.1:p.Ile615Met
NP_001268422.1:p.Ile443Met
NP_001268423.1:p.Ile443Met
LRG_219t1:c.2235T>G
LRG_219:g.22072T>G
LRG_219p1:p.Ile745Met
NC_000002.11:g.48027357T>G
NM_000179.2:c.2235T>G

Protein change:

I443M

Links:

dbSNP: rs556339046

NCBI 1000 Genomes Browser:

rs556339046

Molecular consequence:

NM_000179.3:c.2235T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.1845T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.1329T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.1329T>G - 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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Homo sapiens pericentrin, mRNA (cDNA clone IMAGE:5495146), partial cds
Homo sapiens pericentrin, mRNA (cDNA clone IMAGE:5495146), partial cds
gi|23272845|gb|BC035913.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001175666	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (May 12, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30093976, 32459922 Citation Link,
SCV001358084	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 6, 2018)	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

SCV001175666

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(May 12, 2022)

germline

clinical testing

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

Citation Link,

SCV001358084

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 6, 2018)

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

Citations

PubMed

Clinical genetic testing outcome with multi-gene panel in Asian patients with multiple primary cancers.

Chan GHJ, Ong PY, Low JJH, Kong HL, Ow SGW, Tan DSP, Lim YW, Lim SE, Lee SC.

Oncotarget. 2018 Jul 17;9(55):30649-30660. doi: 10.18632/oncotarget.25769.

PubMed [citation]

PMID:: 30093976
PMCID:: PMC6078133

WWP1 Gain-of-Function Inactivation of PTEN in Cancer Predisposition.

Lee YR, Yehia L, Kishikawa T, Ni Y, Leach B, Zhang J, Panch N, Liu J, Wei W, Eng C, Pandolfi PP.

N Engl J Med. 2020 May 28;382(22):2103-2116. doi: 10.1056/NEJMoa1914919.

PubMed [citation]

PMID:: 32459922
PMCID:: PMC7839065

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV001175666.4

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

Description

The p.I745M variant (also known as c.2235T>G), located in coding exon 4 of the MSH6 gene, results from a T to G substitution at nucleotide position 2235. The isoleucine at codon 745 is replaced by methionine, an amino acid with highly similar properties. This alteration was observed in a cohort of 431 patients with wild-type PTEN who met at least the relaxed diagnostic criteria of the International Cowden Consortium (Lee YR et al. N Engl J Med. 2020 05;382:2103-2116). This alteration has been reported as a variant of unknown significance in an individual with a personal history of breast cancer from a cohort of 1191 cancer index patients who underwent clinical evaluation and testing with multigene panels (Chan GHJ et al. Oncotarget. 2018 Jul;9:30649-30660). This amino acid position is not well 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, SCV001358084.1

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

#	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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