Total submissions: 15
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
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. |
Invitae | RCV000226023 | SCV000284028 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2024-01-28 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 577 of the MLH1 protein (p.Ser577Leu). This variant is present in population databases (rs56185292, gnomAD 0.06%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with breast, ovarian, colorectal or pancreatic cancer (PMID: 25186627, 27601186, 28767289, 30982232, 31360874, 32659497, 32914570). ClinVar contains an entry for this variant (Variation ID: 127619). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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 | RCV000411289 | SCV000488812 | uncertain significance | Colorectal cancer, hereditary nonpolyposis, type 2 | 2016-06-23 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
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, |
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, |
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, |
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. |
Ce |
RCV000656864 | SCV001371043 | uncertain significance | not provided | 2020-06-01 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
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, |
RCV000411289 | SCV004018136 | 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]. |
Baylor Genetics | RCV000411289 | SCV004195060 | uncertain significance | Colorectal cancer, hereditary nonpolyposis, type 2 | 2023-10-12 | criteria provided, single submitter | clinical testing | |
All of Us Research Program, |
RCV003997263 | SCV004843202 | uncertain significance | Lynch syndrome | 2024-01-11 | 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. |
ITMI | RCV000121362 | SCV000085543 | not provided | not specified | 2013-09-19 | no assertion provided | reference population |