Submissions for variant NM_000251.3(MSH2):c.2360T>G (p.Leu787Arg)

dbSNP: rs1558521929

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
University of Washington Department of Laboratory Medicine, University of Washington	RCV000758593	SCV000887342	uncertain significance	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	MSH2 NM_000251.2:c.2360T>G has a 93.3% probability of pathogenicity based on combining prior probability from public data with likelihood ratios of 1.56 to 1 and 1.56 to 1, generated from evidence of seeing this as a somatic mutation in two independent tumors without loss of heterozygosity at the MSH2 locus. See Shirts et al 2018, PMID 29887214.
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	RCV001269395	SCV001449166	pathogenic	Hereditary nonpolyposis colon cancer	2020-09-17	criteria provided, single submitter	clinical testing	Data included in classification: UK family #1. Proband: Breast cancer at age 45, bladder cancer at age 80 (MMR proficient papillary TCC),. Endometrial and colorectal cancer at age 83. Loss of MSH2/MSH6 by IHC in colorectal cancer sample. Proband’s mother: Bowel Cancer at age 83. No molecular testing undertaken. Proband’s daughter: caecal cancer with loss of MSH2/MSH6 by IHC at age 53. MSH2 c.2360T>G p.(Leu787Arg) variant found, along with another MSH2 variant now classified as benign. Proband’s granddaughter: Stage II Colorectal cancer age 29, MMR and MSI results pending. MSH2 c.2360T>G p.(Leu787Arg) variant found. UK family #2. Proband: Caecal cancer MSH2/MSH6 deficient by IHC at age 62. Endometrial cancer (endometrioid adenocarcinoma) at age 51, also MSH2/MSH6 deficient. Breast cancer at age 64. Tubular adenomas. Proband’s brother: Colorectal cancer in 60s, MMR proficient, negative for the familial variant. Ambry individual #1: Uterine tumour with loss of MSH2/MSH6 on IHC, MSI-H and CN-LOH for this variant. MSH2 c.2360T>G p.(Leu787Arg) also identified in germline. (PS4_strong, PP4_strong) Multiple in silico tools predict variant pathogenicity, including Revel: 0.968 (PP3_sup) Variant is absent from GnomAD controls (PM2_sup) Data not included in classification: Ambry individual #2: Colon tumour deficient in MSH2/MSH6 expression by IHC and was MSI-H. MSH2 c.2360T>G p.(Leu787Arg) identified as a somatic change alongside a germline pathogenic MSH2 variant. UK family #1 three affected relatives with the variant (proband, proband’s daughter and proband’s granddaughter): 2 informative meiosis. Shirts et al, 2018 Multifactorial classification of variant as VUS using tumour phenotype data and somatic variants. PMID: 29887214. One classification on ClinVar as VUS by University of Washington (May 2018).
Ambry Genetics	RCV002442567	SCV002733198	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-05-07	criteria provided, single submitter	clinical testing	The p.L787R variant (also known as c.2360T>G), located in coding exon 14 of the MSH2 gene, results from a T to G substitution at nucleotide position 2360. The leucine at codon 787 is replaced by arginine, an amino acid with dissimilar properties. This alteration was identified in the germline of an individual whose uterine tumor displayed high microsatellite instability (MSI-H), loss of both MSH2/MSH6 expression on immunohistochemistry (IHC), and somatic MSH2 CN-LOH (Ambry internal data). This alteration was also identified as somatic along with a germline pathogenic MSH2 variant in a MSI-H colon tumor that displayed loss of MSH2 and MSH6 expression on IHC (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature, 2016 08;536:285-91). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Myriad Genetics, Inc.	RCV003453545	SCV004186605	likely pathogenic	Lynch syndrome 1	2023-08-08	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 33357406]. This variant is expected to disrupt protein structure [Myriad internal data].