Submissions for variant NM_000179.3(MSH6):c.2633T>C (p.Val878Ala)

gnomAD frequency: 0.00448  dbSNP: rs2020912

Total submissions: 36

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000030264	SCV000107978	no known pathogenicity	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability <0.001
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080582	SCV000153945	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000121581	SCV000170356	benign	not specified	2013-10-11	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000157763	SCV000212713	benign	Hereditary cancer-predisposing syndrome	2014-11-18	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.
PreventionGenetics, part of Exact Sciences	RCV000121581	SCV000302872	benign	not specified		criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000157763	SCV000537378	benign	Hereditary cancer-predisposing syndrome	2015-01-02	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000121581	SCV000595842	benign	not specified	2018-09-10	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034495	SCV000604268	benign	not provided	2023-11-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121581	SCV000695820	benign	not specified	2016-04-25	criteria provided, single submitter	clinical testing	Variant summary: Variant affects a non-conserved nucleotide and results in a replacement of a medium size and hydrophobic Valine (V) with a small size and hydrophobic Alanine (A). 2/3 in silico tools predict the variant to be neutral (SNPs&GO and mutation taster were not considered due to low reliability index). The variant was observed in the large and broad cohorts of the ExAC project across diverse ethnicities at an allele frequency of 0.52% which exceeds ~ 36 times the maximal expected allele frequency of a disease causing MSH6 allele (0.0142%). Additionally, 4 homozygous occurrences are also reported in ExAC indicating neutrality. The variant was reported in several patients, however without strong evidence for pathogenicity. Independent functional studies concluded the variant to slightly impair MSH6 MMR functions however a large case control study failed to show association between CRC and the variant (Lipkin_NG_2004). Several clinical diagnostic centers and databases classify variant as Benign (without evidence to independently evaluate). Moreover, UMD lists two co-occurrences with the following pathogenic MSH6 variants: c.3268_3274del (p.Glu1090LysfsX23) and c.3514dup (p.Arg1172LysfsX5). Considering all evidence, the variant was classified as Benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000009486	SCV000743210	benign	Lynch syndrome 5	2017-07-28	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000009486	SCV000744292	benign	Lynch syndrome 5	2015-09-21	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000009486	SCV000745652	likely benign	Lynch syndrome 5	2015-09-22	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000121581	SCV000854909	likely benign	not specified	2018-02-23	criteria provided, single submitter	clinical testing
Mendelics	RCV000009486	SCV001135823	likely benign	Lynch syndrome 5	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034495	SCV001152295	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	MSH6: BP4, BS2
Illumina Laboratory Services, Illumina	RCV000009486	SCV001302726	uncertain significance	Lynch syndrome 5	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001797998	SCV002042043	benign	Breast and/or ovarian cancer	2021-04-27	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000157763	SCV002535758	benign	Hereditary cancer-predisposing syndrome	2020-09-29	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000121581	SCV002552312	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490347	SCV002802151	benign	Endometrial carcinoma; Lynch syndrome 5; Mismatch repair cancer syndrome 3	2022-04-26	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000157763	SCV004014967	benign	Hereditary cancer-predisposing syndrome	2023-04-18	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000009486	SCV004015979	benign	Lynch syndrome 5	2023-07-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000034495	SCV005243564	benign	not provided		criteria provided, single submitter	not provided
OMIM	RCV000009486	SCV000029704	uncertain significance	Lynch syndrome 5	2001-10-01	no assertion criteria provided	literature only
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034495	SCV000043358	no known pathogenicity	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Benign.
ITMI	RCV000121581	SCV000085777	not provided	not specified	2013-09-19	no assertion provided	reference population
CSER _CC_NCGL, University of Washington	RCV000148644	SCV000190359	likely benign	Colorectal / endometrial cancer	2014-06-01	no assertion criteria provided	research
Mayo Clinic Laboratories, Mayo Clinic	RCV000121581	SCV000257226	benign	not specified		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353988	SCV000592611	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The Val878Ala variant has been previously identified in the literature and by our laboratory. More than 39 probands have been cited in the literature including individuals with endometrial cancer, MSI, microsatellite Mutator phenotype (MMP), and individual meeting Amsterdam Criteria for Lynch syndrome (Charames 2000, Barnetson 2008, Jennifer 2008, Wasielewski 2010, Plaschke 2006, Korhonen 2008, Hampel 2006, Ohmiya 2001, Ohmiya 2001, Berends 2002, Peterlongo 2003, Lipkin 2004, Dovrat 2005). However, there was conflicting information as to the relationship of this variant with disease status. This variant was identified in combination with another variant on the other allele in two different individual, one of whom had a nonsense variant (Plaschke 2006, Ohmiya 2001) raising the possibility that this is a benign variant. Furthermore, over 51 control individuals have been identified with this variant in the literature. In one large case control study, 25/2384 cases had this variant and 46/2630 race matched controls (From Northern Israel and Haifa) were carriers of this variant (Lipkin 2004). The variant has also been observed in other populations at lower frequency (dbSNP:rs2020912). This variant is conserved in mammals and other vertebrates but not in fruitfly. In-silico analysis (Sift, AlignGVGD, MAPP) provide conflicting data, and this information is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with absolute certainty but we would lean towards a more likely benign role for this variant.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000009486	SCV000734215	benign	Lynch syndrome 5		no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000157763	SCV000788047	benign	Hereditary cancer-predisposing syndrome	2018-09-11	no assertion criteria provided	clinical testing
Center of Medical Genetics and Primary Health Care	RCV001269491	SCV001449145	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000121581	SCV001905703	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000121581	SCV001920979	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000121581	SCV001957734	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000121581	SCV002036020	benign	not specified		no assertion criteria provided	clinical testing