Submissions for variant NM_000249.4(MLH1):c.1730C>T (p.Ser577Leu)

gnomAD frequency: 0.00003  dbSNP: rs56185292

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656864	SCV000149374	uncertain significance	not provided	2023-02-03	criteria provided, single submitter	clinical testing	Observed in individuals with a personal or family history of Lynch syndrome-associated cancers and in a healthy individual undergoing whole genome sequencing (Chao et al., 2008; Bodian et al., 2014; Lagerstedt-Robinson et al., 2016; Shindo et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Also known as c.1007C>T; p.(Ser336Leu); This variant is associated with the following publications: (PMID: 33471991, 25186627), 30982232, 32914570, 31391288, 24728327, 27601186, 18383312, 28767289, 33281875, 32959997, 27535533, 12799449, 20533529, 22753075)
Ambry Genetics	RCV000115465	SCV000184371	benign	Hereditary cancer-predisposing syndrome	2020-09-08	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226023	SCV000284028	benign	Hereditary nonpolyposis colorectal neoplasms	2025-02-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000411289	SCV000488812	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2016-06-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115465	SCV000537587	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-20	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 577 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with Lynch syndrome, breast, and pancreatic cancer (PMID: 25186627, 27601186, 28767289, 31360874, 32659497, 32914570, 32959997, 33471991), as well as in multiple unaffected individuals reported in pancreatic cancer and breast cancer case-control studies (PMID: 32980694, 33471991). This variant has been identified in 17/282594 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000121362	SCV000592418	uncertain significance	not specified	2015-05-06	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656864	SCV000601362	likely benign	not provided	2023-01-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515241	SCV000611399	uncertain significance	Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2	2017-05-23	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000411289	SCV001310411	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CeGaT Center for Human Genetics Tuebingen	RCV000656864	SCV001371043	uncertain significance	not provided	2020-06-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121362	SCV001572382	uncertain significance	not specified	2022-09-06	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1730C>T (p.Ser577Leu) results in a non-conservative amino acid change located in the C-terminal domain (IPR032189) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6e-05 in 251202 control chromosomes, predominantly at a frequency of 0.00071 within the East Asian subpopulation in the gnomAD database, including 1 homozygote.The variant, c.1730C>T, has been reported in the literature in individuals affected with colorectal cancer and other tumor phenotypes that belong to the Lynch Syndrome tumor spectrum (example: Chao_2008, Lagerstedt-Robinson_2016, Toh_2018, Li_2020, Jiang_2020, Shindo_2017 etc.). However, these reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. The variant has been also reported in the literature in multiple individuals affected with Breast Cancer (example: Tung_2015, Wang_2019 etc.). However, a recent large-scale Breast Cancer study reported the variant in 13/60466 BrC cases and 13/53461 controls, i.e. with a calculated odds ratio of 0.88, which suggests that this variant is not associated with a risk for Breast Cancer (Dorling_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar and classified the variant as VUS (n=8), likely benign (n=1) or benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Myriad Genetics, Inc.	RCV000411289	SCV004018136	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2024-11-25	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: 27363726].
Baylor Genetics	RCV000411289	SCV004195060	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2024-02-27	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997263	SCV004843202	uncertain significance	Lynch syndrome	2024-07-10	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 577 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with Lynch syndrome, breast and pancreatic cancer (PMID: 25186627, 27601186, 28767289, 31360874, 32659497, 32914570, 32959997) and an unaffected individual in a pancreatic cancer case-control study (PMID: 32980694). However, this variant has not shown a significant association with breast cancer in a large case-control study, with an odds ratio reported at 0.884 (95% confidence interval: 0.41 to 1.907, PMID: 33471991). This variant has been identified in 17/282594 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000411289	SCV005402188	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2024-05-22	criteria provided, single submitter	clinical testing	The MLH1 c.1730C>T (p.Ser577Leu) missense change has a maximum subpopulation frequency of 0.07% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with Lynch syndrome-associated tumors (PMID: 27601186; 28767289). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
ITMI	RCV000121362	SCV000085543	not provided	not specified	2013-09-19	no assertion provided	reference population