16-68801670-T-G
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
This summary comes from the ClinGen Evidence Repository: The c.164T>G (p.Val55Gly) variant has been observed in >10 (113) individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; SCV000321508.8, SCV000153979.11). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA157980/MONDO:0007648/007
Frequency
Consequence
NM_004360.5 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.164T>G | p.Val55Gly | missense_variant, splice_region_variant | Exon 3 of 16 | ENST00000261769.10 | NP_004351.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152158Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251390Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135870
GnomAD4 exome AF: 0.000110 AC: 160AN: 1460268Hom.: 0 Cov.: 32 AF XY: 0.000110 AC XY: 80AN XY: 726566
GnomAD4 genome AF: 0.0000723 AC: 11AN: 152158Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74348
ClinVar
Submissions by phenotype
Hereditary diffuse gastric adenocarcinoma Uncertain:2Benign:2
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BS2 (PMID: 30311375) -
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This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
not specified Uncertain:1Benign:2Other:1
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Variant summary: CDH1 c.164T>G (p.Val55Gly) results in a non-conservative amino acid change located in the Cadherin prodomain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. Lack of impact on splicing was confirmed by RNA sequencing studies (Karam_2019). The variant allele was found at a frequency of 0.00011 in 1612426 control chromosomes, predominantly at a frequency of 0.00014 within the Non-Finnish European subpopulation in the gnomAD v4 database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Diffuse Gastric Cancer phenotype (2.8e-05). c.164T>G has been reported in the literature in individuals affected with colon cancer, breast cancer cases and controls and recurrent pregnancy loss (Yurgelun_2017, DeRycke_2017, Quintero-Ronderos_2017, Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. 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: 28944238, 33471991, 31642931, 29016666, 28135145). ClinVar contains an entry for this variant (Variation ID: 132769). Based on the evidence outlined above, the variant was classified as likely benign. -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
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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. -
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not provided Uncertain:1Benign:1
The CDH1 c.164T>G (p.Val55Gly) variant has been reported in the published literature in individuals with colorectal cancer (PMIDs: 28944238 (2017), 28135145 (2017)) and breast cancer (PMID:24969172 (2014)), as well as in one family with a history of both gastric cancer and breast cancer (PMID: 36436516 (2023)). Additionally, this variant was seen in a cohort of reportedly healthy individuals (PMID: 24728327 (2014)). The frequency of this variant in the general population, 0.000054 (7/129106 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
See Variant Classification Assertion Criteria. -
CDH1-related diffuse gastric and lobular breast cancer syndrome Benign:2
The c.164T>G (p.Val55Gly) variant has been observed in >10 (113) individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; SCV000321508.8, SCV000153979.11). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. -
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Breast and/or ovarian cancer Uncertain:1
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CDH1-related disorder Uncertain:1
The CDH1 c.164T>G variant is predicted to result in the amino acid substitution p.Val55Gly. This variant has been reported in an individual with colorectal cancer that harbored a pathogenic MUTYH variant (Table A4, Yurgelun et al. 2017. PubMed ID: 28135145). It has been reported in an individual with breast cancer that harbored variants in other genes (Table S2, Wen et al. 2014. PubMed ID: 24969172). It has been reported in an individual with recurrent pregnancy loss (Tables 1 and 2, Quintero-Ronderos et al. 2017. PubMed ID: 29016666). It has been reported in an individual from a healthy, ancestry diverse cohort (Table S1, Bodian et al. PubMed ID: 24728327). The results of RT-PCR analysis suggest this variant does not impact splicing (eTable, Karam et al. 2019. PubMed ID: 31642931). It has also been reported as a somatically-acquired alteration in a pleomorphic xanthoastrocytoma (Table 1, Chan et al. 2017. PubMed ID: 28699883). This variant is reported in 0.0054% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-68835573-T-G). It has conflicting interpretation for likely benign and uncertain significance in ClinVar. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at