NM_000179.3(MSH6):c.16A>C (p.Thr6Pro) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Mar 28, 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:: RCV000490967.9

Allele description [Variation Report for NM_000179.3(MSH6):c.16A>C (p.Thr6Pro)]

NM_000179.3(MSH6):c.16A>C (p.Thr6Pro)

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.16A>C (p.Thr6Pro)

HGVS:

NC_000002.12:g.47783249A>C
NG_007111.1:g.5103A>C
NM_000179.3:c.16A>CMANE SELECT
NM_001281492.2:c.16A>C
NM_001281493.2:c.-721A>C
NP_000170.1:p.Thr6Pro
NP_000170.1:p.Thr6Pro
NP_001268421.1:p.Thr6Pro
LRG_219t1:c.16A>C
LRG_219:g.5103A>C
LRG_219p1:p.Thr6Pro
NC_000002.11:g.48010388A>C
NM_000179.2:c.16A>C

Protein change:

T6P

Links:

dbSNP: rs200944853

NCBI 1000 Genomes Browser:

rs200944853

Molecular consequence:

NM_001281493.2:c.-721A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000179.3:c.16A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.16A>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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000580276	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jan 20, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26580448, 29684080 Citation Link,
SCV001346620	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 28, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26580448, 29684080, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000580276

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jan 20, 2023)

germline

clinical testing

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

Citation Link,

SCV001346620

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 28, 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

Germline Mutations in Predisposition Genes in Pediatric Cancer.

Zhang J, Walsh MF, Wu G, Edmonson MN, Gruber TA, Easton J, Hedges D, Ma X, Zhou X, Yergeau DA, Wilkinson MR, Vadodaria B, Chen X, McGee RB, Hines-Dowell S, Nuccio R, Quinn E, Shurtleff SA, Rusch M, Patel A, Becksfort JB, Wang S, et al.

N Engl J Med. 2015 Dec 10;373(24):2336-2346. doi: 10.1056/NEJMoa1508054. Epub 2015 Nov 18.

PubMed [citation]

PMID:: 26580448
PMCID:: PMC4734119

Unexpected cancer-predisposition gene variants in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome patients without underlying germline PTEN mutations.

Yehia L, Ni Y, Sesock K, Niazi F, Fletcher B, Chen HJL, LaFramboise T, Eng C.

PLoS Genet. 2018 Apr;14(4):e1007352. doi: 10.1371/journal.pgen.1007352.

PubMed [citation]

PMID:: 29684080
PMCID:: PMC5933810

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000580276.7

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

Description

The p.T6P variant (also known as c.16A>C), located in coding exon 1 of the MSH6 gene, results from an A to C substitution at nucleotide position 16. The threonine at codon 6 is replaced by proline, an amino acid with highly similar properties. This variant has been reported in 1/1120 pediatric cancer patients who underwent whole genome sequencing and/or whole exome sequencing; this patient was diagnosed with high grade glioma (Zhang J et al. N. Engl. J. Med., 2015 Dec;373:2336-2346). In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet., 2018 04;14:e1007352). This amino acid position is well 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, SCV001346620.3

#	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 threonine with proline at codon 6 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals with glioma (PMID: 26580448) and unspecified cancer (PMID: 29684080). This variant has been identified in 2/276232 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

Last Updated: Oct 20, 2024

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