Submissions for variant NM_000251.3(MSH2):c.1661G>A (p.Ser554Asn)

dbSNP: rs63750597

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000570315	SCV000669713	pathogenic	Hereditary cancer-predisposing syndrome	2022-07-14	criteria provided, single submitter	clinical testing	The c.1661G>A pathogenic mutation (also known as p.S554N), located in coding exon 10 of the MSH2 gene, results from a G to A substitution at nucleotide position 1661. The serine at codon 554 is replaced by asparagine, an amino acid with highly similar properties. However, this change occurs in the last base pair of exon 10, which makes it likely to have some effect on normal mRNA splicing. This mutation was previously identified in one family fulfilling Amsterdam criteria; further functional analysis of this alteration showed abolishment of the native donor site and a deletion of the last 81 base pairs of exon 10 (Perez-Cabornero L et al. Eur. J. Cancer. 2009 May;45:1485-93; Pérez-Cabornero L et al. Cancer Prev Res (Phila). 2011 Oct;4:1546-55). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000802215	SCV000942036	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-07-15	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 554 of the MSH2 protein (p.Ser554Asn). RNA analysis indicates that this missense change induces altered splicing and likely results in the loss of 81 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs63750597, gnomAD 0.0009%). This missense change has been observed in individual(s) with Lynch syndrome-associated cancers (PMID: 21778331, 23523604). It has also been observed to segregate with disease in related individuals. Invitae’s Lynch syndrome clinical variant model, which takes into account the clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH2 variant, predicts that it is pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model developed at Invitae that incorporates the clinical features of 1,370,736 individuals referred for testing at Invitae. ClinVar contains an entry for this variant (Variation ID: 483664). 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in the activation of a cryptic splice site in exon 10 (PMID: 19250818). For these reasons, this variant has been classified as Pathogenic.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV001310202	SCV001499803	likely pathogenic	Lynch syndrome 1	2020-04-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002497211	SCV002809739	likely pathogenic	Lynch syndrome 1; Muir-Torré syndrome; Mismatch repair cancer syndrome 2	2021-07-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001310202	SCV004187973	pathogenic	Lynch syndrome 1	2023-08-03	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 18561205].