NM_000179.3(MSH6):c.773T>C (p.Ile258Thr) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jul 31, 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:: RCV001174609.2

Allele description [Variation Report for NM_000179.3(MSH6):c.773T>C (p.Ile258Thr)]

NM_000179.3(MSH6):c.773T>C (p.Ile258Thr)

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.773T>C (p.Ile258Thr)

HGVS:

NC_000002.12:g.47798756T>C
NG_007111.1:g.20610T>C
NM_000179.3:c.773T>CMANE SELECT
NM_001281492.2:c.383T>C
NM_001281493.2:c.-134T>C
NM_001281494.2:c.-134T>C
NP_000170.1:p.Ile258Thr
NP_000170.1:p.Ile258Thr
NP_001268421.1:p.Ile128Thr
LRG_219t1:c.773T>C
LRG_219:g.20610T>C
LRG_219p1:p.Ile258Thr
NC_000002.11:g.48025895T>C
NM_000179.2:c.773T>C

Protein change:

I128T

Links:

dbSNP: rs1553412195

NCBI 1000 Genomes Browser:

rs1553412195

Molecular consequence:

NM_001281493.2:c.-134T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001281494.2:c.-134T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000179.3:c.773T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.383T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001337806	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Jan 13, 2020)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23621914, 27601186, 31269945 Citation Link,
SCV005090474	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 31, 2024)	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

SCV001337806

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Jan 13, 2020)

germline

clinical testing

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

Citation Link,

SCV005090474

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jul 31, 2024)

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

CoDP: predicting the impact of unclassified genetic variants in MSH6 by the combination of different properties of the protein.

Terui H, Akagi K, Kawame H, Yura K.

J Biomed Sci. 2013 Apr 28;20:25. doi: 10.1186/1423-0127-20-25.

PubMed [citation]

PMID:: 23621914
PMCID:: PMC3651391

Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population.

Lagerstedt-Robinson K, Rohlin A, Aravidis C, Melin B, Nordling M, Stenmark-Askmalm M, Lindblom A, Nilbert M.

Oncol Rep. 2016 Nov;36(5):2823-2835. doi: 10.3892/or.2016.5060. Epub 2016 Sep 1.

PubMed [citation]

PMID:: 27601186

See all PubMed Citations (4)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001337806.1

#	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.773T>C (p.Ile258Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251164 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.773T>C has been reported in the literature in individuals affected with Lynch Syndrome or FAP (Lagerstedt-Robinson_2016, Kim_2019). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with a pathogenic variant has been reported (MLH1 c.1989G>A; Lagerstedt-Robinson_2016), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories 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

From Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, SCV005090474.1

#	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: Sep 29, 2024

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