Total submissions: 11
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV003993844 | SCV004812909 | likely benign | CDH1-related diffuse gastric and lobular breast cancer syndrome | 2023-09-25 | reviewed by expert panel | curation | The c.1170C>T (p.Asn390=) variant results in a synonymous change in exon 9 of CDH1. This is a silent variant that occurs at a position that is not highly conserved and for which splicing predictors do not suggest an impact on splicing (BP4, BP7). This variant is absent from the gnomAD population database v3.1.2. This variant was identified in 70 individuals without DGC, LBC, SRC tumours and whose families do not suggest HDGC (BS2; PMID: 30287823, 36436516, and internal laboratory contributors). In summary, this variant is classified as likely benign based on ACMG/AMP criteria applied as likely benign specified by the CDH1 Variant Curation Expert Panel: BS2, BP4, BP7. |
Ambry Genetics | RCV000163189 | SCV000213710 | likely benign | Hereditary cancer-predisposing syndrome | 2015-07-01 | 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. |
Labcorp Genetics |
RCV000230370 | SCV000288423 | likely benign | Hereditary diffuse gastric adenocarcinoma | 2024-01-24 | criteria provided, single submitter | clinical testing | |
Illumina Laboratory Services, |
RCV000230370 | SCV000398562 | uncertain significance | Hereditary diffuse gastric adenocarcinoma | 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. |
Gene |
RCV001283953 | SCV000528197 | likely benign | not provided | 2020-10-14 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV000163189 | SCV000684334 | likely benign | Hereditary cancer-predisposing syndrome | 2016-02-25 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000425400 | SCV001363014 | likely benign | not specified | 2020-01-31 | criteria provided, single submitter | clinical testing | |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV001283953 | SCV001469478 | likely benign | not provided | 2020-01-20 | criteria provided, single submitter | clinical testing | |
European Reference Network on Genetic Tumour Risk Syndromes |
RCV000230370 | SCV003926751 | uncertain significance | Hereditary diffuse gastric adenocarcinoma | 2022-08-01 | criteria provided, single submitter | clinical testing | PM2 (PMID: 30311375) |
Myriad Genetics, |
RCV000230370 | SCV005405765 | benign | Hereditary diffuse gastric adenocarcinoma | 2024-09-18 | criteria provided, single submitter | clinical testing | This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. |
Department of Pathology and Laboratory Medicine, |
RCV001354451 | SCV001549069 | likely benign | Malignant tumor of breast | no assertion criteria provided | clinical testing | The CDH1 p.Asn390= variant was not identified in the literature nor was it identified in the Cosmic, MutDB, Insight Colon Cancer Gene Variant Database, and Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs766505270) as “With other allele”, ClinVar (as likely benign by Ambry Genetics, Invitae, and GeneDx, and as uncertain significance by Illumina), and in Clinvitae databases. The variant was identified in control databases in 2 of 246248 chromosomes at a frequency of 0.000008 in the following populations: East Asian in 1 of 17248 chromosomes (freq. 0.00006) and European (Non-Finnish) in 1 of 111702 chromosomes (freq. 0.000009), increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Asn390= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. |