rs267607785
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4
The NM_000249.4(MLH1):c.678-3T>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000249.4 splice_region, splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MLH1 | NM_000249.4 | c.678-3T>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000231790.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLH1 | ENST00000231790.8 | c.678-3T>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_000249.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 22
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 04, 2023 | For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in multiple RNA products (PMID: 32356167). ClinVar contains an entry for this variant (Variation ID: 90325). This variant is also known as IVS8-3T>A. This variant has been observed in individuals with clinical features of Lynch syndrome (PMID: 16379545, 32356167; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 8 of the MLH1 gene. It does not directly change the encoded amino acid sequence of the MLH1 protein. It affects a nucleotide within the consensus splice site. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 08, 2022 | The c.678-3T>A intronic pathogenic variant results from a T to A substitution 3 nucleotides upstream from coding exon 9 in the MLH1 gene. This nucleotide position is poorly conserved in available vertebrate species. This alteration was identified in an individual whose family history met Amsterdam II criteria for Lynch syndrome and endometrial tumor demonstrated loss of both MLH1 and PMS2 on immunohistochemistry (IHC) (Ambry internal data). In one study, this variant was observed to segregate with early-onset colon cancer in a proband and her three affected siblings (Loader S et al. Genet. Test. 2005;9:313-9). In another study, this alteration was detected in an unaffected individual with a family history of colon cancer (O'Leary E et al. Am. J. Digest. Dis. 2014;1(1):62-66). In addition, this alteration segregated with disease in a family meeting Amsterdam II criteria with the proband showing loss of MHL1 protein expression on IHC in her MSI-H tumor and RNA studies demonstrated abnormal splicing resulting in both coding exon 9 as well as coding exon 9, 10 skipping (Yang C et al. Fam Cancer, 2020 10;19:315-322). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Of note, this alteration is also designated as IVS8-3T>A in the published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 08, 2017 | This variant is denoted MLH1 c.678-3T>A or IVS8-3T>A and consists of a T>A nucleotide substitution at the -3 position of intron 8 of the MLH1 gene. Multiple in silico models predict this variant to weaken the nearby natural splice acceptor site and to possibly cause abnormal gene splicing; however, in the absence of RNA or functional studies, the actual effect of this variant is unknown. This variant was observed in at least two individuals with a personal and/or family history of early-onset colorectal cancer, and was shown to segregate with colorectal cancers in four members of one of the families (Loader 2005, OÂ’Leary 2014). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant to be of uncertain significance due to insufficient evidence for classification (Thompson 2014). MLH1 c.678-3T>A was not observed in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project).The thymine (T) nucleotide that is altered is not conserved. Based on currently available evidence, it is unclear whether MLH1 c.678-3T>A is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at