NM_000179.3(MSH6):c.2579C>T (p.Ser860Phe) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 7, 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:: RCV000164156.6

Allele description [Variation Report for NM_000179.3(MSH6):c.2579C>T (p.Ser860Phe)]

NM_000179.3(MSH6):c.2579C>T (p.Ser860Phe)

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.2579C>T (p.Ser860Phe)

HGVS:

NC_000002.12:g.47800562C>T
NG_007111.1:g.22416C>T
NM_000179.3:c.2579C>TMANE SELECT
NM_001281492.2:c.2189C>T
NM_001281493.2:c.1673C>T
NM_001281494.2:c.1673C>T
NP_000170.1:p.Ser860Phe
NP_000170.1:p.Ser860Phe
NP_001268421.1:p.Ser730Phe
NP_001268422.1:p.Ser558Phe
NP_001268423.1:p.Ser558Phe
LRG_219t1:c.2579C>T
LRG_219:g.22416C>T
LRG_219p1:p.Ser860Phe
NC_000002.11:g.48027701C>T
NM_000179.2:c.2579C>T
p.S860F

Protein change:

S558F

Links:

dbSNP: rs370412074

NCBI 1000 Genomes Browser:

rs370412074

Molecular consequence:

NM_000179.3:c.2579C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.2189C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.1673C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.1673C>T - 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

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Ubiquitin-conjugating enzyme E2 G2 [Caligus rogercresseyi]
Ubiquitin-conjugating enzyme E2 G2 [Caligus rogercresseyi]
gi|225711384|gb|ACO11538.1|

Protein
ubiquitin conjugating enzyme (nucleomorph) [Proteomonas sulcata]
ubiquitin conjugating enzyme (nucleomorph) [Proteomonas sulcata]
gi|81159224|gb|ABB55888.1|

Protein
probable WRKY transcription factor 7 [Manihot esculenta]
probable WRKY transcription factor 7 [Manihot esculenta]
gi|1216260352|ref|XP_021614182.1|

Protein
Homo sapiens cDNA clone IMAGE:9052033
Homo sapiens cDNA clone IMAGE:9052033
gi|219521218|gb|BC143524.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000214772	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jul 28, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30267214, 32002723 Citation Link,
SCV004357659	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 7, 2023)	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

SCV000214772

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jul 28, 2023)

germline

clinical testing

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

Citation Link,

SCV004357659

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 7, 2023)

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

Citations

PubMed

Rare loss of function variants in candidate genes and risk of colorectal cancer.

Rosenthal EA, Shirts BH, Amendola LM, Horike-Pyne M, Robertson PD, Hisama FM, Bennett RL, Dorschner MO, Nickerson DA, Stanaway IB, Nassir R, Vickers KT, Li C, Grady WM, Peters U, Jarvik GP; NHLBI GO Exome Sequencing Project..

Hum Genet. 2018 Oct;137(10):795-806. doi: 10.1007/s00439-018-1938-4. Epub 2018 Sep 28.

PubMed [citation]

PMID:: 30267214
PMCID:: PMC6283057

Prevalence of CNV-neutral structural genomic rearrangements in MLH1, MSH2, and PMS2 not detectable in routine NGS diagnostics.

Morak M, Steinke-Lange V, Massdorf T, Benet-Pages A, Locher M, Laner A, Kayser K, Aretz S, Holinski-Feder E.

Fam Cancer. 2020 Apr;19(2):161-167. doi: 10.1007/s10689-020-00159-4.

PubMed [citation]

PMID:: 32002723

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000214772.8

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

Description

The p.S860F variant (also known as c.2579C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 2579. The serine at codon 860 is replaced by phenylalanine, an amino acid with highly dissimilar properties. In one study, this variant was detected in 0/165 colorectal cancer and/or polyposis patients and was identified in 1/2512 control individuals from a healthy population database (Rosenthal EA et al. Hum Genet, 2018 Oct;137:795-806). This alteration has also been reported in a German patient who met Bethesda criteria and whose tumor showed loss of expression of the MSH2 and MSH6 proteins (Morak M et al. Fam Cancer, 2020 04;19:161-167). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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, SCV004357659.1

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

Description

This missense variant replaces serine with phenylalanine at codon 860 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 1/249360 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 29, 2024

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