NM_000179.3(MSH6):c.2260A>C (p.Thr754Pro) AND Lynch syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 23, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003998496.2

Allele description [Variation Report for NM_000179.3(MSH6):c.2260A>C (p.Thr754Pro)]

NM_000179.3(MSH6):c.2260A>C (p.Thr754Pro)

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.2260A>C (p.Thr754Pro)

Other names:

p.T754P:ACT>CCT

HGVS:

NC_000002.12:g.47800243A>C
NG_007111.1:g.22097A>C
NM_000179.3:c.2260A>CMANE SELECT
NM_001281492.2:c.1870A>C
NM_001281493.2:c.1354A>C
NM_001281494.2:c.1354A>C
NP_000170.1:p.Thr754Pro
NP_000170.1:p.Thr754Pro
NP_001268421.1:p.Thr624Pro
NP_001268422.1:p.Thr452Pro
NP_001268423.1:p.Thr452Pro
LRG_219t1:c.2260A>C
LRG_219:g.22097A>C
LRG_219p1:p.Thr754Pro
NC_000002.11:g.48027382A>C
NM_000179.2:c.2260A>C

Protein change:

T452P

Links:

dbSNP: rs545057945

NCBI 1000 Genomes Browser:

rs545057945

Molecular consequence:

NM_000179.3:c.2260A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.1870A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.1354A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.1354A>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Lynch syndrome
Identifiers:: MONDO: MONDO:0005835; MedGen: C4552100

Recent activity

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phosducin, partial [Voeltzkowia yamagishii]
phosducin, partial [Voeltzkowia yamagishii]
gi|815860098|gb|AKE49021.1|

Protein
RecName: Full=Triosephosphate isomerase; Short=TIM; AltName: Full=Triose-phospha...
RecName: Full=Triosephosphate isomerase; Short=TIM; AltName: Full=Triose-phosphate isomerase
gi|1351275|sp|P48499.1|TPIS_LEIME

Protein
Lambdapapillomavirus
Lambdapapillomavirus
A genus of DNA viruses in the family papillomaviridae, causing mucosal and cutaneous lesions in cats and dogs. Canine oral papillomavirus is the type species....<br/>Year introduced: 2007

MeSH

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004841916	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Oct 23, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29684080, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004841916

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Oct 23, 2023)

germline

clinical testing

PubMed (2)
[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	5	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

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

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

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004841916.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	PubMed (2)

Description

This missense variant replaces threonine with proline at codon 754 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 29684080). This variant has been identified in 2/251058 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	108544	not provided	not provided		5	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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