NM_000249.4(MLH1):c.1321G>A (p.Ala441Thr) AND Hereditary cancer-predisposing syndrome

Germline classification:: Benign (5 submissions)
Last evaluated:: Nov 22, 2022
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:: RCV000115456.15

Allele description [Variation Report for NM_000249.4(MLH1):c.1321G>A (p.Ala441Thr)]

NM_000249.4(MLH1):c.1321G>A (p.Ala441Thr)

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.1321G>A (p.Ala441Thr)

Other names:

p.A441T:GCT>ACT

HGVS:

NC_000003.12:g.37025919G>A
NG_007109.2:g.37570G>A
NM_000249.4:c.1321G>AMANE SELECT
NM_001167617.3:c.1027G>A
NM_001167618.3:c.598G>A
NM_001167619.3:c.598G>A
NM_001258271.2:c.1321G>A
NM_001258273.2:c.598G>A
NM_001258274.3:c.598G>A
NM_001354615.2:c.598G>A
NM_001354616.2:c.598G>A
NM_001354617.2:c.598G>A
NM_001354618.2:c.598G>A
NM_001354619.2:c.598G>A
NM_001354620.2:c.1027G>A
NM_001354621.2:c.298G>A
NM_001354622.2:c.298G>A
NM_001354623.2:c.298G>A
NM_001354624.2:c.247G>A
NM_001354625.2:c.247G>A
NM_001354626.2:c.247G>A
NM_001354627.2:c.247G>A
NM_001354628.2:c.1321G>A
NM_001354629.2:c.1222G>A
NM_001354630.2:c.1321G>A
NP_000240.1:p.Ala441Thr
NP_000240.1:p.Ala441Thr
NP_001161089.1:p.Ala343Thr
NP_001161090.1:p.Ala200Thr
NP_001161091.1:p.Ala200Thr
NP_001245200.1:p.Ala441Thr
NP_001245202.1:p.Ala200Thr
NP_001245203.1:p.Ala200Thr
NP_001341544.1:p.Ala200Thr
NP_001341545.1:p.Ala200Thr
NP_001341546.1:p.Ala200Thr
NP_001341547.1:p.Ala200Thr
NP_001341548.1:p.Ala200Thr
NP_001341549.1:p.Ala343Thr
NP_001341550.1:p.Ala100Thr
NP_001341551.1:p.Ala100Thr
NP_001341552.1:p.Ala100Thr
NP_001341553.1:p.Ala83Thr
NP_001341554.1:p.Ala83Thr
NP_001341555.1:p.Ala83Thr
NP_001341556.1:p.Ala83Thr
NP_001341557.1:p.Ala441Thr
NP_001341558.1:p.Ala408Thr
NP_001341559.1:p.Ala441Thr
LRG_216t1:c.1321G>A
LRG_216:g.37570G>A
LRG_216p1:p.Ala441Thr
NC_000003.11:g.37067410G>A
NM_000249.3:c.1321G>A
NM_001258274.1:c.598G>A
P40692:p.Ala441Thr
p.A441T

Protein change:

A100T

Links:

UniProtKB: P40692#VAR_012920; dbSNP: rs63750365

NCBI 1000 Genomes Browser:

rs63750365

Molecular consequence:

NM_000249.4:c.1321G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.1027G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.598G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.598G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.1321G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.598G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.598G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.598G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.598G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.598G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.598G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.598G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.1027G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.298G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.298G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.298G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354624.2:c.247G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354625.2:c.247G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354626.2:c.247G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354627.2:c.247G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.1321G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.1222G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.1321G>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
SCV000184608	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Benign (Jan 17, 2019)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11524701, 16451135, 17510385, 21404117 Citation Link,
SCV000788017	True Health Diagnostics	no assertion criteria provided	Likely benign (Aug 30, 2017)	germline	clinical testing
SCV000902604	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (Oct 15, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002528638	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Benign (Mar 4, 2021)	germline	curation	Citation Link,
SCV002819232	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (Nov 22, 2022)	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, curation

Citations

PubMed

The frequency of hereditary defective mismatch repair in a prospective series of unselected colorectal carcinomas.

Cunningham JM, Kim CY, Christensen ER, Tester DJ, Parc Y, Burgart LJ, Halling KC, McDonnell SK, Schaid DJ, Walsh Vockley C, Kubly V, Nelson H, Michels VV, Thibodeau SN.

Am J Hum Genet. 2001 Oct;69(4):780-90. Epub 2001 Aug 24. Erratum in: Am J Hum Genet 2001 Nov;69(5):1160.

PubMed [citation]

PMID:: 11524701
PMCID:: PMC1226064

Germline MSH2 and MLH1 mutational spectrum including large rearrangements in HNPCC families from Poland (update study).

Kurzawski G, Suchy J, Lener M, Kłujszo-Grabowska E, Kładny J, Safranow K, Jakubowska K, Jakubowska A, Huzarski T, Byrski T, Debniak T, Cybulski C, Gronwald J, Oszurek O, Oszutowska D, Kowalska E, Góźdź S, Niepsuj S, Słomski R, Pławski A, Łacka-Wojciechowska A, Rozmiarek A, et al.

Clin Genet. 2006 Jan;69(1):40-7.

PubMed [citation]

PMID:: 16451135

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000184608.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

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 True Health Diagnostics, SCV000788017.1

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

#	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, SCV000902604.1

#	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, SCV002528638.1

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

#	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 Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C., SCV002819232.1

#	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

Last Updated: Oct 8, 2024

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