NM_000179.3(MSH6):c.968C>G (p.Thr323Ser) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jun 21, 2022
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:: RCV000562475.8

Allele description [Variation Report for NM_000179.3(MSH6):c.968C>G (p.Thr323Ser)]

NM_000179.3(MSH6):c.968C>G (p.Thr323Ser)

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.968C>G (p.Thr323Ser)

HGVS:

NC_000002.12:g.47798951C>G
NG_007111.1:g.20805C>G
NM_000179.3:c.968C>GMANE SELECT
NM_001281492.2:c.578C>G
NM_001281493.2:c.62C>G
NM_001281494.2:c.62C>G
NP_000170.1:p.Thr323Ser
NP_000170.1:p.Thr323Ser
NP_001268421.1:p.Thr193Ser
NP_001268422.1:p.Thr21Ser
NP_001268423.1:p.Thr21Ser
LRG_219t1:c.968C>G
LRG_219:g.20805C>G
LRG_219p1:p.Thr323Ser
NC_000002.11:g.48026090C>G
NM_000179.2:c.968C>G

Protein change:

T193S

Links:

dbSNP: rs777890307

NCBI 1000 Genomes Browser:

rs777890307

Molecular consequence:

NM_000179.3:c.968C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.578C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.62C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.62C>G - 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
SCV000669972	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jun 21, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000913027	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 8, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23047549, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000669972

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jun 21, 2022)

germline

clinical testing

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

Citation Link,

SCV000913027

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 8, 2022)

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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Lynch Syndrome Germline Mutations in Breast Cancer: Next Generation Sequencing Case-Control Study of 1,263 Participants.

Nikitin AG, Chudakova DA, Enikeev RF, Sakaeva D, Druzhkov M, Shigapova LH, Brovkina OI, Shagimardanova EI, Gusev OA, Gordiev MG.

Front Oncol. 2020;10:666. doi: 10.3389/fonc.2020.00666.

PubMed [citation]

PMID:: 32547938
PMCID:: PMC7273971

Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer.

Pal T, Akbari MR, Sun P, Lee JH, Fulp J, Thompson Z, Coppola D, Nicosia S, Sellers TA, McLaughlin J, Risch HA, Rosen B, Shaw P, Schildkraut J, Narod SA.

Br J Cancer. 2012 Nov 6;107(10):1783-90. doi: 10.1038/bjc.2012.452. Epub 2012 Oct 9.

PubMed [citation]

PMID:: 23047549
PMCID:: PMC3493867

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000669972.5

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

Description

The p.T323S variant (also known as c.968C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 968. The threonine at codon 323 is replaced by serine, an amino acid with similar properties. This variant has been identified in one individual from a cohort of 711 Russian hereditary breast cancer patients (Nikitin AG et al. Front Oncol, 2020 May;10:666). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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, SCV000913027.4

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

Description

This missense variant replaces threonine with serine at codon 323 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 ovarian cancer (PMID: 23047549). This variant has been identified in 1/251378 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: Sep 1, 2024

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