NM_000249.4(MLH1):c.1040C>A (p.Thr347Asn) AND Hereditary cancer-predisposing syndrome

Germline classification:: Benign/Likely benign (3 submissions)
Last evaluated:: Oct 19, 2020
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:: RCV000115449.12

Allele description [Variation Report for NM_000249.4(MLH1):c.1040C>A (p.Thr347Asn)]

NM_000249.4(MLH1):c.1040C>A (p.Thr347Asn)

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.1040C>A (p.Thr347Asn)

Other names:

p.T347N:ACT>AAT

HGVS:

NC_000003.12:g.37025638C>A
NG_007109.2:g.37289C>A
NM_000249.4:c.1040C>AMANE SELECT
NM_001167617.3:c.746C>A
NM_001167618.3:c.317C>A
NM_001167619.3:c.317C>A
NM_001258271.2:c.1040C>A
NM_001258273.2:c.317C>A
NM_001258274.3:c.317C>A
NM_001354615.2:c.317C>A
NM_001354616.2:c.317C>A
NM_001354617.2:c.317C>A
NM_001354618.2:c.317C>A
NM_001354619.2:c.317C>A
NM_001354620.2:c.746C>A
NM_001354621.2:c.17C>A
NM_001354622.2:c.17C>A
NM_001354623.2:c.17C>A
NM_001354624.2:c.-35C>A
NM_001354625.2:c.-35C>A
NM_001354626.2:c.-35C>A
NM_001354627.2:c.-35C>A
NM_001354628.2:c.1040C>A
NM_001354629.2:c.941C>A
NM_001354630.2:c.1040C>A
NP_000240.1:p.Thr347Asn
NP_000240.1:p.Thr347Asn
NP_001161089.1:p.Thr249Asn
NP_001161090.1:p.Thr106Asn
NP_001161091.1:p.Thr106Asn
NP_001245200.1:p.Thr347Asn
NP_001245202.1:p.Thr106Asn
NP_001245203.1:p.Thr106Asn
NP_001341544.1:p.Thr106Asn
NP_001341545.1:p.Thr106Asn
NP_001341546.1:p.Thr106Asn
NP_001341547.1:p.Thr106Asn
NP_001341548.1:p.Thr106Asn
NP_001341549.1:p.Thr249Asn
NP_001341550.1:p.Thr6Asn
NP_001341551.1:p.Thr6Asn
NP_001341552.1:p.Thr6Asn
NP_001341557.1:p.Thr347Asn
NP_001341558.1:p.Thr314Asn
NP_001341559.1:p.Thr347Asn
LRG_216t1:c.1040C>A
LRG_216:g.37289C>A
LRG_216p1:p.Thr347Asn
NC_000003.11:g.37067129C>A
NM_000249.3:c.1040C>A
p.T347N

Protein change:

T106N

Links:

dbSNP: rs201541505

NCBI 1000 Genomes Browser:

rs201541505

Molecular consequence:

NM_001354624.2:c.-35C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-35C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-35C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-35C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.1040C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.746C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.317C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.317C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.1040C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.317C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.317C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.317C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.317C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.317C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.317C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.317C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.746C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.17C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.17C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.17C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.1040C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.941C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.1040C>A - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000212876	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Benign (Dec 13, 2014)	germline	clinical testing	Citation Link,
SCV000910763	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Jul 14, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002528616	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Benign (Oct 19, 2020)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 22949379, 27435373 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000212876

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Benign
(Dec 13, 2014)

germline

clinical testing

Citation Link,

SCV000910763

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(Jul 14, 2016)

germline

clinical testing

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

SCV002528616

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Benign
(Oct 19, 2020)

germline

curation

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

Citation Link

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, curation

Citations

PubMed

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

A multifactorial likelihood model for MMR gene variant classification incorporating probabilities based on sequence bioinformatics and tumor characteristics: a report from the Colon Cancer Family Registry.

Thompson BA, Goldgar DE, Paterson C, Clendenning M, Walters R, Arnold S, Parsons MT, Michael D W, Gallinger S, Haile RW, Hopper JL, Jenkins MA, Lemarchand L, Lindor NM, Newcomb PA, Thibodeau SN; Colon Cancer Family Registry, Young JP, Buchanan DD, Tavtigian SV, Spurdle AB.

Hum Mutat. 2013 Jan;34(1):200-9. doi: 10.1002/humu.22213. Epub 2012 Oct 11.

PubMed [citation]

PMID:: 22949379
PMCID:: PMC3538359

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000212876.7

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

Description

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

#	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, SCV000910763.1

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

#	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 Sema4, Sema4, SCV002528616.1

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

#	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: Jan 19, 2025

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