Submissions for variant NM_000249.4(MLH1):c.1060G>A (p.Gly354Ser)

gnomAD frequency: 0.00001  dbSNP: rs752962453

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000815372	SCV000955822	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 354 of the MLH1 protein (p.Gly354Ser). This variant is present in population databases (rs752962453, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 658532). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MLH1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV001009815	SCV001169929	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-20	criteria provided, single submitter	clinical testing	The p.G354S variant (also known as c.1060G>A), located in coding exon 12 of the MLH1 gene, results from a G to A substitution at nucleotide position 1060. The glycine at codon 354 is replaced by serine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001264495	SCV001442674	uncertain significance	not specified	2020-10-29	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1060G>A (p.Gly354Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.3e-05 in 227668 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1060G>A has been reported in the literature in individuals affected with hereditary breast and/or ovarian cancer and with kidney renal papillary cell carcinoma (e.g. Yehia_2018, Schubert_2019). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV002249525	SCV002520210	uncertain significance	not provided	2022-05-11	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with renal cancer (Yehia 2018); This variant is associated with the following publications: (PMID: 29684080, 30426508)
All of Us Research Program, National Institutes of Health	RCV004001776	SCV004840945	uncertain significance	Lynch syndrome	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 354 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with kidney renal papillary cell carcinoma (PMID: 29684080), and an individual affected with breast and/or ovarian cancer (PMID: 30426508). This variant has been identified in 3/227668 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.