Submissions for variant NM_000179.3(MSH6):c.3801+5G>A

gnomAD frequency: 0.00004  dbSNP: rs201080919

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166530	SCV000217331	likely benign	Hereditary cancer-predisposing syndrome	2019-01-24	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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	RCV000524188	SCV000262055	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000203730	SCV000266086	likely benign	Lynch syndrome	2016-12-20	criteria provided, single submitter	clinical testing	Communication from other laboratories about other patients with this variant and no family history of colorectal cancer. Splicing anlaysis indicates 95% full length product.
GeneDx	RCV000587152	SCV000279111	likely benign	not provided	2019-10-16	criteria provided, single submitter	clinical testing	In silico analysis, which includes splice predictors and evolutionary conservation, 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.; Observed in individuals with colorectal and breast cancers (Shirts 2016, Tung 2016, Yurgelun 2017); This variant is associated with the following publications: (PMID: 28135145, 31642931, 25318351, 26976419, 26845104)
Illumina Laboratory Services, Illumina	RCV000411771	SCV000430980	uncertain significance	Lynch syndrome 5	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Counsyl	RCV000411771	SCV000488861	uncertain significance	Lynch syndrome 5	2016-09-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001260253	SCV000695890	likely benign	not specified	2024-03-11	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3801+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: One predict the variant weakens the canonical 5' splicing donor site. Three predict the variant abolishes the canonical 5' splicing donor site. However, RNA studies demonstrate this variant has no abnormal splicing (Karam_2019). The variant allele was found at a frequency of 8.8e-05 in 251178 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome (8.8e-05 vs 0.00014), allowing no conclusion about variant significance. c.3801+5G>A has been reported in the literature in individuals affected with breast cancer, colorectal cancer, Lynch Syndrome as well as in healthy individuals and also as a VUS in settings of multigene panel testing (example, Shirts_2016, Tung_2016, Yorczyk_2015, Yurgelun_2017, Karam_2019, de Oliveira_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. At-least two co-occurrences with other pathogenic variant(s) have been observed at our laboratory (RB1 c.1399C>T, p.Arg467X; BRCA1 c.2411_2412delAG, p.Gln804LeufsX5), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34445333, 31642931, 26845104, 26976419, 25318351, 28135145, 35534704). ClinVar contains an entry for this variant (Variation ID: 186876). Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000166530	SCV000902693	likely benign	Hereditary cancer-predisposing syndrome	2016-12-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587152	SCV002046098	likely benign	not provided	2021-01-30	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000166530	SCV002528071	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-22	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000411771	SCV004018878	likely benign	Lynch syndrome 5	2023-03-28	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].
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000587152	SCV001552322	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MSH6 c.3801+5G>A variant was identified in 3 of 4640 proband chromosomes (frequency: 0.0006) from individuals or families with breast, ovarian or colon cancer (Shirts 2016, Yorczyk 2014, Tung 2016). The variant was also identified in the following databases: dbSNP (ID: rs201080919) as “With other allele” and ClinVar (2x as likely benign by Ambry Genetics and University of Washington, 5x as uncertain significance by Invitae, GeneDx, Counsyl, Integrated Genetics, Illumina Clinical services) The variant was not identified in COGR, Cosmic, MutDB, UMD-LSDB, Zhejiang Colon Cancer Database, or Insight Hereditary Tumors Database. The variant was identified in control databases in 22 of 245988 chromosomes at a frequency of 0.00009 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 5476 chromosomes (freq: 0.0002), Latino in 7 of 33544 chromosomes (freq: 0.0002), European Non-Finnish in 9 of 111508 chromosomes (freq: 0.00008), Ashkenazi Jewish in 5 of 9848 chromosomes (freq: 0.0005), while the variant was not observed in the African, East Asian, European Finnish, or South Asian populations. The c.3801+5G>A variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.