NM_000179.3(MSH6):c.3539C>T (p.Ser1180Leu) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 1, 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:: RCV003594644.2

Allele description [Variation Report for NM_000179.3(MSH6):c.3539C>T (p.Ser1180Leu)]

NM_000179.3(MSH6):c.3539C>T (p.Ser1180Leu)

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.3539C>T (p.Ser1180Leu)

HGVS:

NC_000002.12:g.47805010C>T
NG_007111.1:g.26864C>T
NG_008397.1:g.105666G>A
NM_000179.3:c.3539C>TMANE SELECT
NM_001281492.2:c.3149C>T
NM_001281493.2:c.2633C>T
NM_001281494.2:c.2633C>T
NM_001406795.1:c.3635C>T
NM_001406796.1:c.3539C>T
NM_001406797.1:c.3242C>T
NM_001406798.1:c.3365C>T
NM_001406799.1:c.3014C>T
NM_001406800.1:c.3539C>T
NM_001406801.1:c.3242C>T
NM_001406802.1:c.3635C>T
NM_001406803.1:c.2675C>T
NM_001406804.1:c.3461C>T
NM_001406805.1:c.3242C>T
NM_001406806.1:c.3014C>T
NM_001406807.1:c.3014C>T
NM_001406808.1:c.3539C>T
NM_001406809.1:c.3539C>T
NM_001406811.1:c.2633C>T
NM_001406812.1:c.2633C>T
NM_001406813.1:c.3545C>T
NM_001406814.1:c.2633C>T
NM_001406815.1:c.2633C>T
NM_001406816.1:c.2633C>T
NM_001406817.1:c.1973C>T
NM_001406818.1:c.3242C>T
NM_001406819.1:c.3242C>T
NM_001406820.1:c.3242C>T
NM_001406821.1:c.3242C>T
NM_001406822.1:c.3242C>T
NM_001406823.1:c.2633C>T
NM_001406824.1:c.3242C>T
NM_001406825.1:c.3242C>T
NM_001406826.1:c.3371C>T
NM_001406827.1:c.3242C>T
NM_001406828.1:c.3242C>T
NM_001406829.1:c.2633C>T
NM_001406830.1:c.3242C>T
NM_001406831.1:c.320C>T
NM_001406832.1:c.386C>T
NM_001407362.1:c.1484C>T
NP_000170.1:p.Ser1180Leu
NP_000170.1:p.Ser1180Leu
NP_001268421.1:p.Ser1050Leu
NP_001268422.1:p.Ser878Leu
NP_001268423.1:p.Ser878Leu
NP_001393724.1:p.Ser1212Leu
NP_001393725.1:p.Ser1180Leu
NP_001393726.1:p.Ser1081Leu
NP_001393727.1:p.Ser1122Leu
NP_001393728.1:p.Ser1005Leu
NP_001393729.1:p.Ser1180Leu
NP_001393730.1:p.Ser1081Leu
NP_001393731.1:p.Ser1212Leu
NP_001393732.1:p.Ser892Leu
NP_001393733.1:p.Ser1154Leu
NP_001393734.1:p.Ser1081Leu
NP_001393735.1:p.Ser1005Leu
NP_001393736.1:p.Ser1005Leu
NP_001393737.1:p.Ser1180Leu
NP_001393738.1:p.Ser1180Leu
NP_001393740.1:p.Ser878Leu
NP_001393741.1:p.Ser878Leu
NP_001393742.1:p.Ser1182Leu
NP_001393743.1:p.Ser878Leu
NP_001393744.1:p.Ser878Leu
NP_001393745.1:p.Ser878Leu
NP_001393746.1:p.Ser658Leu
NP_001393747.1:p.Ser1081Leu
NP_001393748.1:p.Ser1081Leu
NP_001393749.1:p.Ser1081Leu
NP_001393750.1:p.Ser1081Leu
NP_001393751.1:p.Ser1081Leu
NP_001393752.1:p.Ser878Leu
NP_001393753.1:p.Ser1081Leu
NP_001393754.1:p.Ser1081Leu
NP_001393755.1:p.Ser1124Leu
NP_001393756.1:p.Ser1081Leu
NP_001393757.1:p.Ser1081Leu
NP_001393758.1:p.Ser878Leu
NP_001393759.1:p.Ser1081Leu
NP_001393760.1:p.Ser107Leu
NP_001393761.1:p.Ser129Leu
NP_001394291.1:p.Ser495Leu
LRG_219t1:c.3539C>T
LRG_219:g.26864C>T
LRG_219p1:p.Ser1180Leu
NC_000002.11:g.48032149C>T
NM_000179.2:c.3539C>T
NR_176256.1:n.2469C>T
NR_176257.1:n.3800C>T
NR_176258.1:n.3729C>T
NR_176259.1:n.3628C>T
NR_176260.1:n.1573C>T

Protein change:

S1005L

Molecular consequence:

NM_000179.3:c.3539C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.3149C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.2633C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.2633C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406795.1:c.3635C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406796.1:c.3539C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406797.1:c.3242C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406798.1:c.3365C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406799.1:c.3014C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406800.1:c.3539C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406801.1:c.3242C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406802.1:c.3635C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406803.1:c.2675C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406804.1:c.3461C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406805.1:c.3242C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406806.1:c.3014C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406807.1:c.3014C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406808.1:c.3539C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406809.1:c.3539C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406811.1:c.2633C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406812.1:c.2633C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406813.1:c.3545C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406814.1:c.2633C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406815.1:c.2633C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406816.1:c.2633C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406817.1:c.1973C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406818.1:c.3242C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406819.1:c.3242C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406820.1:c.3242C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406821.1:c.3242C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406822.1:c.3242C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406823.1:c.2633C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406824.1:c.3242C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406825.1:c.3242C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406826.1:c.3371C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406827.1:c.3242C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406828.1:c.3242C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406829.1:c.2633C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406830.1:c.3242C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406831.1:c.320C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406832.1:c.386C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407362.1:c.1484C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_176256.1:n.2469C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176257.1:n.3800C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176258.1:n.3729C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176259.1:n.3628C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Hereditary nonpolyposis colorectal neoplasms
Identifiers:: MeSH: D003123; MedGen: C0009405

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RecName: Full=Extracellular tyrosine-protein kinase PKDCC; AltName: Full=Protein...
RecName: Full=Extracellular tyrosine-protein kinase PKDCC; AltName: Full=Protein kinase domain-containing protein, cytoplasmic; AltName: Full=Protein kinase-like protein SgK493; AltName: Full=Sugen kinase 493; AltName: Full=Vertebrate lonesome kinase; Flags: Precursor
gi|292495024|sp|Q504Y2.2|PKDCC_HUMA

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004314745	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 1, 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

SCV004314745

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 1, 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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004314745.1

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

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MSH6 protein function. ClinVar contains an entry for this variant (Variation ID: 2567454). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1180 of the MSH6 protein (p.Ser1180Leu).

#	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

ClinVar

Relating variation to medicine