NM_000179.3(MSH6):c.1814C>G (p.Thr605Ser) AND not provided

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Aug 23, 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:: RCV000587763.10

Allele description [Variation Report for NM_000179.3(MSH6):c.1814C>G (p.Thr605Ser)]

NM_000179.3(MSH6):c.1814C>G (p.Thr605Ser)

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.1814C>G (p.Thr605Ser)

Other names:

p.T605S:ACT>AGT

HGVS:

NC_000002.12:g.47799797C>G
NG_007111.1:g.21651C>G
NM_000179.3:c.1814C>GMANE SELECT
NM_001281492.2:c.1424C>G
NM_001281493.2:c.908C>G
NM_001281494.2:c.908C>G
NP_000170.1:p.Thr605Ser
NP_000170.1:p.Thr605Ser
NP_001268421.1:p.Thr475Ser
NP_001268422.1:p.Thr303Ser
NP_001268423.1:p.Thr303Ser
LRG_219t1:c.1814C>G
LRG_219:g.21651C>G
LRG_219p1:p.Thr605Ser
NC_000002.11:g.48026936C>G
NM_000179.2:c.1814C>G
p.T605S

Protein change:

T303S

Links:

dbSNP: rs587781616

NCBI 1000 Genomes Browser:

rs587781616

Molecular consequence:

NM_000179.3:c.1814C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.1424C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.908C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.908C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

Clear Turn Off Turn On

Paraburkholderia phenoliruptrix BR3459a chromosome 2, complete sequence
Paraburkholderia phenoliruptrix BR3459a chromosome 2, complete sequence
gi|407237448|gb|CP003864.1|

Nucleotide

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
SCV000211349	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Aug 23, 2023)	germline	clinical testing	Citation Link,
SCV000695796	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Aug 8, 2017)	germline	clinical testing	LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000889461	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Apr 24, 2019)	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

SCV000211349

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Aug 23, 2023)

germline

clinical testing

Citation Link,

SCV000695796

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Aug 8, 2017)

germline

clinical testing

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV000889461

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Uncertain significance
(Apr 24, 2019)

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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]

PMID:: 26467025
PMCID:: PMC4737317

Details of each submission

From GeneDx, SCV000211349.16

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

Description

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal or family history of breast or unspecified cancer as well as in unaffected control individuals (Rizzolo et al., 2019; Tsaousis et al., 2019; Akcay et al., 2020; Li et al., 2020; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 31159747, 31391288, 30613976, 33471991, 17531815, 21120944, 32658311)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000695796.1

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

Description

Variant summary: The MSH6 c.1814C>G (p.Thr605Ser) variant located in the DNA mismatch repair protein MutS, connector domain (via InterPro) involves the alteration of a conserved nucleotide and 3/5 in silico tools predict a benign outcome. However, these predictions have yet to be functionally assessed. This variant was found in 15/276888 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000103 (13/126470). This frequency is comparable to the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421), suggesting this variant could be a rare benign polymorphism found in population(s) of European (Non-Finnish) origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Although, multiple clinical diagnostic laboratories and a reputable database classified this variant as uncertain significance. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000889461.3

#	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

ClinVar

Relating variation to medicine