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NM_000249.4(MLH1):c.2258T>C (p.Phe753Ser) AND Hereditary cancer-predisposing syndrome

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Sep 25, 2023
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:
RCV004522890.1

Allele description [Variation Report for NM_000249.4(MLH1):c.2258T>C (p.Phe753Ser)]

NM_000249.4(MLH1):c.2258T>C (p.Phe753Ser)

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.2258T>C (p.Phe753Ser)
HGVS:
  • NC_000003.12:g.37050640T>C
  • NG_007109.2:g.62291T>C
  • NG_053016.1:g.131178A>G
  • NM_000249.4:c.2258T>CMANE SELECT
  • NM_001167617.3:c.1964T>C
  • NM_001167618.3:c.1535T>C
  • NM_001167619.3:c.1535T>C
  • NM_001258271.2:c.2051T>C
  • NM_001258273.2:c.1535T>C
  • NM_001258274.3:c.1535T>C
  • NM_001354615.2:c.1535T>C
  • NM_001354616.2:c.1535T>C
  • NM_001354617.2:c.1535T>C
  • NM_001354618.2:c.1535T>C
  • NM_001354619.2:c.1535T>C
  • NM_001354620.2:c.1964T>C
  • NM_001354621.2:c.1235T>C
  • NM_001354622.2:c.1235T>C
  • NM_001354623.2:c.1235T>C
  • NM_001354624.2:c.1184T>C
  • NM_001354625.2:c.1184T>C
  • NM_001354626.2:c.1184T>C
  • NM_001354627.2:c.1184T>C
  • NM_001354628.2:c.2165T>C
  • NM_001354629.2:c.2159T>C
  • NM_001354630.2:c.2093T>C
  • NP_000240.1:p.Phe753Ser
  • NP_000240.1:p.Phe753Ser
  • NP_001161089.1:p.Phe655Ser
  • NP_001161090.1:p.Phe512Ser
  • NP_001161091.1:p.Phe512Ser
  • NP_001245200.1:p.Phe684Ser
  • NP_001245202.1:p.Phe512Ser
  • NP_001245203.1:p.Phe512Ser
  • NP_001341544.1:p.Phe512Ser
  • NP_001341545.1:p.Phe512Ser
  • NP_001341546.1:p.Phe512Ser
  • NP_001341547.1:p.Phe512Ser
  • NP_001341548.1:p.Phe512Ser
  • NP_001341549.1:p.Phe655Ser
  • NP_001341550.1:p.Phe412Ser
  • NP_001341551.1:p.Phe412Ser
  • NP_001341552.1:p.Phe412Ser
  • NP_001341553.1:p.Phe395Ser
  • NP_001341554.1:p.Phe395Ser
  • NP_001341555.1:p.Phe395Ser
  • NP_001341556.1:p.Phe395Ser
  • NP_001341557.1:p.Phe722Ser
  • NP_001341558.1:p.Phe720Ser
  • NP_001341559.1:p.Phe698Ser
  • LRG_216t1:c.2258T>C
  • LRG_216:g.62291T>C
  • LRG_216p1:p.Phe753Ser
  • NC_000003.11:g.37092131T>C
  • NM_000249.3:c.2258T>C
Protein change:
F395S
Links:
dbSNP: rs587778993
NCBI 1000 Genomes Browser:
rs587778993
Molecular consequence:
  • NM_000249.4:c.2258T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167617.3:c.1964T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167618.3:c.1535T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167619.3:c.1535T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258271.2:c.2051T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258273.2:c.1535T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258274.3:c.1535T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354615.2:c.1535T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354616.2:c.1535T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354617.2:c.1535T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354618.2:c.1535T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354619.2:c.1535T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354620.2:c.1964T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354621.2:c.1235T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354622.2:c.1235T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354623.2:c.1235T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354624.2:c.1184T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354625.2:c.1184T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354626.2:c.1184T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354627.2:c.1184T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354628.2:c.2165T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354629.2:c.2159T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354630.2:c.2093T>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

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV005033259Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(Sep 25, 2023) 		germlineclinical testing

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From Ambry Genetics, SCV005033259.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The p.F753S variant (also known as c.2258T>C), located in coding exon 19 of the MLH1 gene, results from a T to C substitution at nucleotide position 2258. The phenylalanine at codon 753 is replaced by serine, an amino acid with highly dissimilar properties. This variant has been identified in a proband who met Amsterdam I criteria for Lynch syndrome and tumor demonstrated high microsatellite instability with loss of PMS2 expression by immunohistochemistry (external laboratory communication). This variant has also been identified in at least one proband whose Lynch syndrome-associated tumor demonstrated loss of PMS2 expression by immunohistochemistry (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. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 7, 2024