NM_000179.3(MSH6):c.38A>C (p.Lys13Thr) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jun 21, 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:: RCV000569787.13

Allele description [Variation Report for NM_000179.3(MSH6):c.38A>C (p.Lys13Thr)]

NM_000179.3(MSH6):c.38A>C (p.Lys13Thr)

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.38A>C (p.Lys13Thr)

Other names:

p.K13T:AAG>ACG

HGVS:

NC_000002.12:g.47783271A>C
NG_007111.1:g.5125A>C
NM_000179.3:c.38A>CMANE SELECT
NM_001281492.2:c.38A>C
NM_001281493.2:c.-699A>C
NP_000170.1:p.Lys13Thr
NP_000170.1:p.Lys13Thr
NP_001268421.1:p.Lys13Thr
LRG_219t1:c.38A>C
LRG_219:g.5125A>C
LRG_219p1:p.Lys13Thr
NC_000002.11:g.48010410A>C
NM_000179.2:c.38A>C
P52701:p.Lys13Thr

Protein change:

K13T

Links:

UniProtKB: P52701#VAR_038032; dbSNP: rs41294988

NCBI 1000 Genomes Browser:

rs41294988

Molecular consequence:

NM_001281493.2:c.-699A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000179.3:c.38A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.38A>C - 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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000662392	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Nov 18, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000685459	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 21, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18033691, 31965077, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000662392

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Nov 18, 2022)

germline

clinical testing

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

Citation Link,

SCV000685459

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 21, 2023)

germline

clinical testing

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

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

Classification of ambiguous mutations in DNA mismatch repair genes identified in a population-based study of colorectal cancer.

Barnetson RA, Cartwright N, van Vliet A, Haq N, Drew K, Farrington S, Williams N, Warner J, Campbell H, Porteous ME, Dunlop MG.

Hum Mutat. 2008 Mar;29(3):367-74.

PubMed [citation]

PMID:: 18033691

Two integrated and highly predictive functional analysis-based procedures for the classification of MSH6 variants in Lynch syndrome.

Drost M, Tiersma Y, Glubb D, Kathe S, van Hees S, Calléja F, Zonneveld JBM, Boucher KM, Ramlal RPE, Thompson BA, Rasmussen LJ, Greenblatt MS, Lee A, Spurdle AB, Tavtigian SV, de Wind N.

Genet Med. 2020 May;22(5):847-856. doi: 10.1038/s41436-019-0736-2. Epub 2020 Jan 22.

PubMed [citation]

PMID:: 31965077
PMCID:: PMC7200593

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000662392.6

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

Description

The p.K13T variant (also known as c.38A>C), located in coding exon 1 of the MSH6 gene, results from an A to C substitution at nucleotide position 38. The lysine at codon 13 is replaced by threonine, an amino acid with similar properties. This alteration was identified in one of 932 colorectal cancer patients diagnosed under 55 years of age and was not seen in any of the 1104 control individuals; however, this individual’s tumor showed microsatellite stability and presence of MSH6 staining on immunohistochemistry and was therefore classified as "undefined" (Barnetson RA et al. Hum. Mutat. 2008 Mar;29:367-74). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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, SCV000685459.5

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

Description

This missense variant replaces lysine with threonine at codon 13 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant retained approximately 50% of wild-type mismatch repair activity (PMID: 31965077). This variant has been reported in an individual with mismatch repair stable colorectal cancer (PMID: 18033691). 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

Last Updated: Oct 8, 2024

ClinVar

Relating variation to medicine