ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.845C>G (p.Ala282Gly)

gnomAD frequency: 0.00001  dbSNP: rs63750360
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075884 SCV000106900 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability 0.001-0.049
Mendelics RCV000987158 SCV001136387 benign Colorectal cancer, hereditary nonpolyposis, type 2 2019-05-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV001017839 SCV001178996 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-02 criteria provided, single submitter clinical testing The p.A282G variant (also known as c.845C>G), located in coding exon 10 of the MLH1 gene, results from a C to G substitution at nucleotide position 845. The alanine at codon 282 is replaced by glycine, an amino acid with similar properties. This alteration has been detected in several individuals with colorectal cancer (Shin YK et al. Hum. Mutat., 2004 Oct;24:351; Roh SA et al. J. Korean Med. Sci., 2003 Jun;18:387-91). In addition, two studies based on in silico model predictions showed this alteration to be both benign and pathogenic, and a third study showed that this alteration may have some impact on splicing (van der Velde KJ et al. Hum. Mutat., 2015 Jul;36:712-9; Lucci-Cordisco E et al. Cancer Biomark, 2006;2:11-27; Soukarieh O et al. PLoS Genet., 2016 Jan;12:e1005756). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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