NM_000249.4(MLH1):c.421C>T (p.Pro141Ser) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 19, 2020
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:: RCV001306573.4

Allele description [Variation Report for NM_000249.4(MLH1):c.421C>T (p.Pro141Ser)]

NM_000249.4(MLH1):c.421C>T (p.Pro141Ser)

Gene:

MLH1:mutL homolog 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.421C>T (p.Pro141Ser)

HGVS:

NC_000003.12:g.37007031C>T
NG_007109.2:g.18682C>T
NM_000249.4:c.421C>TMANE SELECT
NM_001167617.3:c.127C>T
NM_001167618.3:c.-303C>T
NM_001167619.3:c.-211C>T
NM_001258271.2:c.421C>T
NM_001258273.2:c.-303C>T
NM_001258274.3:c.-303C>T
NM_001354615.2:c.-211C>T
NM_001354616.2:c.-211C>T
NM_001354617.2:c.-303C>T
NM_001354618.2:c.-303C>T
NM_001354619.2:c.-303C>T
NM_001354620.2:c.127C>T
NM_001354621.2:c.-396C>T
NM_001354622.2:c.-509C>T
NM_001354623.2:c.-509C>T
NM_001354624.2:c.-406C>T
NM_001354625.2:c.-314C>T
NM_001354626.2:c.-406C>T
NM_001354627.2:c.-406C>T
NM_001354628.2:c.421C>T
NM_001354629.2:c.322C>T
NM_001354630.2:c.421C>T
NP_000240.1:p.Pro141Ser
NP_001161089.1:p.Pro43Ser
NP_001245200.1:p.Pro141Ser
NP_001341549.1:p.Pro43Ser
NP_001341557.1:p.Pro141Ser
NP_001341558.1:p.Pro108Ser
NP_001341559.1:p.Pro141Ser
LRG_216:g.18682C>T
NC_000003.11:g.37048522C>T

Protein change:

P108S

Links:

dbSNP: rs63750977

NCBI 1000 Genomes Browser:

rs63750977

Molecular consequence:

NM_001167618.3:c.-303C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-211C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-303C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-303C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-211C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-211C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-303C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-303C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-303C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-396C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-509C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-509C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-406C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-314C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-406C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-406C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.421C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.127C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.421C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.127C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.421C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.322C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.421C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

Recent activity

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uncharacterized protein LOC112031151 [Quercus suber]
uncharacterized protein LOC112031151 [Quercus suber]
gi|1344071628|ref|XP_023919605.1|

Protein
calcium-dependent protein kinase SK5-like [Cucurbita maxima]
calcium-dependent protein kinase SK5-like [Cucurbita maxima]
gi|1281057143|ref|XP_022970875.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001495951	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 19, 2020)	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

SCV001495951

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 19, 2020)

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, SCV001495951.3

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

Description

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) performed at Invitae indicates that this missense variant is not expected to disrupt MLH1 protein function. 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. This variant has not been reported in the literature in individuals with MLH1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with serine at codon 141 of the MLH1 protein (p.Pro141Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine.

#	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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