NM_000249.4(MLH1):c.2248T>C (p.Tyr750His) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 4, 2024
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:: RCV000581139.6

Allele description [Variation Report for NM_000249.4(MLH1):c.2248T>C (p.Tyr750His)]

NM_000249.4(MLH1):c.2248T>C (p.Tyr750His)

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.2248T>C (p.Tyr750His)

HGVS:

NC_000003.12:g.37050630T>C
NG_007109.2:g.62281T>C
NG_053016.1:g.131188A>G
NM_000249.4:c.2248T>CMANE SELECT
NM_001167617.3:c.1954T>C
NM_001167618.3:c.1525T>C
NM_001167619.3:c.1525T>C
NM_001258271.2:c.2041T>C
NM_001258273.2:c.1525T>C
NM_001258274.3:c.1525T>C
NM_001354615.2:c.1525T>C
NM_001354616.2:c.1525T>C
NM_001354617.2:c.1525T>C
NM_001354618.2:c.1525T>C
NM_001354619.2:c.1525T>C
NM_001354620.2:c.1954T>C
NM_001354621.2:c.1225T>C
NM_001354622.2:c.1225T>C
NM_001354623.2:c.1225T>C
NM_001354624.2:c.1174T>C
NM_001354625.2:c.1174T>C
NM_001354626.2:c.1174T>C
NM_001354627.2:c.1174T>C
NM_001354628.2:c.2155T>C
NM_001354629.2:c.2149T>C
NM_001354630.2:c.2083T>C
NP_000240.1:p.Tyr750His
NP_000240.1:p.Tyr750His
NP_001161089.1:p.Tyr652His
NP_001161090.1:p.Tyr509His
NP_001161091.1:p.Tyr509His
NP_001245200.1:p.Tyr681His
NP_001245202.1:p.Tyr509His
NP_001245203.1:p.Tyr509His
NP_001341544.1:p.Tyr509His
NP_001341545.1:p.Tyr509His
NP_001341546.1:p.Tyr509His
NP_001341547.1:p.Tyr509His
NP_001341548.1:p.Tyr509His
NP_001341549.1:p.Tyr652His
NP_001341550.1:p.Tyr409His
NP_001341551.1:p.Tyr409His
NP_001341552.1:p.Tyr409His
NP_001341553.1:p.Tyr392His
NP_001341554.1:p.Tyr392His
NP_001341555.1:p.Tyr392His
NP_001341556.1:p.Tyr392His
NP_001341557.1:p.Tyr719His
NP_001341558.1:p.Tyr717His
NP_001341559.1:p.Tyr695His
LRG_216t1:c.2248T>C
LRG_216:g.62281T>C
LRG_216p1:p.Tyr750His
NC_000003.11:g.37092121T>C
NM_000249.3:c.2248T>C

Protein change:

Y392H

Links:

dbSNP: rs777054430

NCBI 1000 Genomes Browser:

rs777054430

Molecular consequence:

NM_000249.4:c.2248T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.1954T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.1525T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.1525T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.2041T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.1525T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.1525T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.1525T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.1525T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.1525T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.1525T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.1525T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.1954T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.1225T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.1225T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.1225T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354624.2:c.1174T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354625.2:c.1174T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354626.2:c.1174T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354627.2:c.1174T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.2155T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.2149T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.2083T>C - 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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000684806	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 30, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002728815	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Apr 4, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000684806

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Sep 30, 2018)

germline

clinical testing

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

SCV002728815

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Apr 4, 2024)

germline

clinical testing

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

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

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

Clinical relevance of pathogenic germline variants in mismatch repair genes in Chinese breast cancer patients.

Hu L, Sun J, Li Z, Qu Z, Liu Y, Wan Q, Liu J, Ding X, Zang F, Zhang J, Yao L, Xu Y, Wang Y, Xie Y.

NPJ Breast Cancer. 2022 Apr 21;8(1):52. doi: 10.1038/s41523-022-00417-x.

PubMed [citation]

PMID:: 35449176
PMCID:: PMC9023502

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000684806.2

#	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 Ambry Genetics, SCV002728815.3

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

Description

The p.Y750H variant (also known as c.2248T>C), located in coding exon 19 of the MLH1 gene, results from a T to C substitution at nucleotide position 2248. The tyrosine at codon 750 is replaced by histidine, an amino acid with similar properties. This variant has been identified in a cohort of 8085 Chinese breast cancer patients (Hu L et al. NPJ Breast Cancer, 2022 Apr;8:52). Based on internal structural analysis, Y750H destabilizes protein-ligand and protein-protein interaction properties (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

#	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