NM_000249.4(MLH1):c.46G>C (p.Val16Leu) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 4, 2022
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:: RCV000554111.9

Allele description [Variation Report for NM_000249.4(MLH1):c.46G>C (p.Val16Leu)]

NM_000249.4(MLH1):c.46G>C (p.Val16Leu)

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.46G>C (p.Val16Leu)

HGVS:

NC_000003.12:g.36993593G>C
NG_007109.2:g.5244G>C
NG_008418.1:g.4712C>G
NM_000249.4:c.46G>CMANE SELECT
NM_001167617.3:c.-471G>C
NM_001167618.3:c.-900G>C
NM_001167619.3:c.-813G>C
NM_001258271.2:c.46G>C
NM_001258273.2:c.-587G>C
NM_001258274.3:c.-1050G>C
NM_001354615.2:c.-581G>C
NM_001354616.2:c.-581G>C
NM_001354617.2:c.-673G>C
NM_001354618.2:c.-905G>C
NM_001354619.2:c.-1029G>C
NM_001354620.2:c.-239G>C
NM_001354621.2:c.-998G>C
NM_001354622.2:c.-1111G>C
NM_001354623.2:c.-1020G>C
NM_001354624.2:c.-781G>C
NM_001354625.2:c.-679G>C
NM_001354626.2:c.-776G>C
NM_001354627.2:c.-1008G>C
NM_001354628.2:c.46G>C
NM_001354629.2:c.46G>C
NM_001354630.2:c.46G>C
NP_000240.1:p.Val16Leu
NP_000240.1:p.Val16Leu
NP_001245200.1:p.Val16Leu
NP_001341557.1:p.Val16Leu
NP_001341558.1:p.Val16Leu
NP_001341559.1:p.Val16Leu
LRG_216t1:c.46G>C
LRG_216:g.5244G>C
LRG_216p1:p.Val16Leu
NC_000003.11:g.37035084G>C
NM_000249.3:c.46G>C

Protein change:

V16L

Links:

dbSNP: rs776643257

NCBI 1000 Genomes Browser:

rs776643257

Molecular consequence:

NM_001167617.3:c.-471G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-900G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-813G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-587G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-1050G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-581G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-581G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-673G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-905G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-1029G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-239G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-998G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-1111G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-1020G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-781G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-679G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-776G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-1008G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.46G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.46G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.46G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.46G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.46G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000625168	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 4, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31386297, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000625168

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 4, 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

Germline mismatch repair gene variants analyzed by universal sequencing in Japanese cancer patients.

Kiyozumi Y, Matsubayashi H, Horiuchi Y, Higashigawa S, Oishi T, Abe M, Ohnami S, Urakami K, Nagashima T, Kusuhara M, Miyake H, Yamaguchi K.

Cancer Med. 2019 Sep;8(12):5534-5543. doi: 10.1002/cam4.2432. Epub 2019 Aug 6.

PubMed [citation]

PMID:: 31386297
PMCID:: PMC6745857

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, SCV000625168.7

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

Description

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 16 of the MLH1 protein (p.Val16Leu). This variant is present in population databases (rs776643257, gnomAD 0.006%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 31386297). ClinVar contains an entry for this variant (Variation ID: 455439). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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.

#	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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