NM_000179.3(MSH6):c.2452C>T (p.Leu818Phe) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Mar 17, 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:: RCV000220336.7

Allele description [Variation Report for NM_000179.3(MSH6):c.2452C>T (p.Leu818Phe)]

NM_000179.3(MSH6):c.2452C>T (p.Leu818Phe)

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.2452C>T (p.Leu818Phe)

HGVS:

NC_000002.12:g.47800435C>T
NG_007111.1:g.22289C>T
NM_000179.3:c.2452C>TMANE SELECT
NM_001281492.2:c.2062C>T
NM_001281493.2:c.1546C>T
NM_001281494.2:c.1546C>T
NP_000170.1:p.Leu818Phe
NP_000170.1:p.Leu818Phe
NP_001268421.1:p.Leu688Phe
NP_001268422.1:p.Leu516Phe
NP_001268423.1:p.Leu516Phe
LRG_219t1:c.2452C>T
LRG_219:g.22289C>T
LRG_219p1:p.Leu818Phe
NC_000002.11:g.48027574C>T
NM_000179.2:c.2452C>T

Protein change:

L516F

Links:

dbSNP: rs786203612

NCBI 1000 Genomes Browser:

rs786203612

Molecular consequence:

NM_000179.3:c.2452C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.2062C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.1546C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.1546C>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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Thermus thermophilus HB27 plasmid pTT27, complete sequence
Thermus thermophilus HB27 plasmid pTT27, complete sequence
gi|46197920|gb|AE017222.1|

Nucleotide
maturase, partial (chloroplast) [Ozothamnus secundiflorus]
maturase, partial (chloroplast) [Ozothamnus secundiflorus]
gi|451769534|gb|AGF44758.1|

Protein
LOC124904444 [Homo sapiens]
LOC124904444 [Homo sapiens]
Gene ID:124904444

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000276651	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Mar 17, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001340305	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 10, 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

SCV000276651

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Mar 17, 2023)

germline

clinical testing

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

Citation Link,

SCV001340305

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 10, 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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Exome sequencing followed by large-scale genotyping suggests a limited role for moderately rare risk factors of strong effect in schizophrenia.

Need AC, McEvoy JP, Gennarelli M, Heinzen EL, Ge D, Maia JM, Shianna KV, He M, Cirulli ET, Gumbs CE, Zhao Q, Campbell CR, Hong L, Rosenquist P, Putkonen A, Hallikainen T, Repo-Tiihonen E, Tiihonen J, Levy DL, Meltzer HY, Goldstein DB.

Am J Hum Genet. 2012 Aug 10;91(2):303-12. doi: 10.1016/j.ajhg.2012.06.018. Epub 2012 Aug 2.

PubMed [citation]

PMID:: 22863191
PMCID:: PMC3415532

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 Ambry Genetics, SCV000276651.9

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

Description

The p.L818F variant (also known as c.2452C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 2452. The leucine at codon 818 is replaced by phenylalanine, an amino acid with highly similar properties. 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, SCV001340305.2

#	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 leucine with phenylalanine at codon 818 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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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