Submissions for variant NM_000249.4(MLH1):c.1007G>A (p.Gly336Asp)

gnomAD frequency: 0.00001  dbSNP: rs587781750

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129956	SCV000184780	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-26	criteria provided, single submitter	clinical testing	The p.G336D variant (also known as c.1007G>A), located in coding exon 11 of the MLH1 gene, results from a G to A substitution at nucleotide position 1007. The glycine at codon 336 is replaced by aspartic acid, an amino acid with similar properties. This alteration was detected in 1/60 Brazilian patients diagnosed with colorectal cancer, who fulfilled either Bethesda or Amsterdam criteria (Schneider NB et al. Cancer Med. 2018 May;7:2078-2088). 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.
Invitae	RCV000196459	SCV000254343	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 336 of the MLH1 protein (p.Gly336Asp). This variant is present in population databases (rs587781750, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 28828701, 29575718, 30238922, 35220195). ClinVar contains an entry for this variant (Variation ID: 141442). 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 expected to disrupt MLH1 protein function with a positive 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.
Counsyl	RCV000411750	SCV000488303	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2016-02-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129956	SCV000684707	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-08	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with aspartic acid at codon 336 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with Lynch syndrome (PMID: 29575718) and an individual affected with endometrial cancer (PMID: 30238922). This variant has been identified in 3/251288 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.
GeneDx	RCV001568035	SCV001791830	uncertain significance	not provided	2023-06-05	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with Lynch syndrome-related cancers, as well as individuals with a personal or family history of breast/ovarian cancer (Soares et al., 2017; Zidan et al., 2017; Schneider et al., 2018; Ozdemir et al., 2019; Bora et al., 2022); This variant is associated with the following publications: (PMID: 29575718, 28932927, 30238922, 22753075, 28828701, 35220195)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226208	SCV003922581	uncertain significance	not specified	2023-03-14	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1007G>A (p.Gly336Asp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251288 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1007G>A has been reported in the literature in individuals affected with breast cancer, endometrial cancer, or colorectal cancer without strong evidence of causality (Bora_2022, Ozdemir_2019, Schneider_2018, Soares_2018, Zidan_2017). These reports do not provide unequivocal conclusions about association of the variant with prostate cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV000411750	SCV004018129	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-14	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
All of Us Research Program, National Institutes of Health	RCV003997537	SCV004840939	uncertain significance	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with aspartic acid at codon 336 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with Lynch syndrome (PMID: 29575718) and an individual affected with endometrial cancer (PMID: 30238922). This variant has been identified in 3/251288 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.