Variant: NM_004360.4(CDH1):c.1008G>T (p.Glu336Asp)

CA280990

18453 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

UUID: f17d1590-599b-49d7-a1e0-273ed56fef12

Approved on: 2024-11-25

Published on: 2024-12-17

HGVS expressions

NM_004360.4:c.1008G>T
NM_004360.4(CDH1):c.1008G>T (p.Glu336Asp)
NC_000016.10:g.68811859G>T
CM000678.2:g.68811859G>T
NC_000016.9:g.68845762G>T
CM000678.1:g.68845762G>T
NC_000016.8:g.67403263G>T
NG_008021.1:g.79568G>T
ENST00000261769.10:c.1008G>T
ENST00000261769.9:c.1008G>T
ENST00000422392.6:c.1008G>T
ENST00000561751.1:c.630G>T
ENST00000562836.5:n.1079G>T
ENST00000566510.5:c.852G>T
ENST00000566612.5:c.1008G>T
ENST00000611625.4:c.1008G>T
ENST00000612417.4:c.1008G>T
ENST00000621016.4:c.1008G>T
NM_004360.3:c.1008G>T
NM_001317184.1:c.1008G>T
NM_001317185.1:c.-608G>T
NM_001317186.1:c.-812G>T
NM_004360.5:c.1008G>T
NM_001317184.2:c.1008G>T
NM_001317185.2:c.-608G>T
NM_001317186.2:c.-812G>T

Likely Pathogenic

• Met criteria codes: PS3 PS4_Moderate PVS1_Moderate PM2_Supporting

• Not Met criteria codes: BS4 BS3 BS1 BS2 BP5 BP7 BP2 BP3 BP1 BP4 PS2 PS1 PP4 PP1 PP2 PP3 PM3 PM4 PM5 PM1 PM6 BA1

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen CDH1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 3.1

Evidence submitted by expert panel

CDH1 VCEP

The c.1008G>T (p.Glu336Asp) variant results in a G to non-G change at the last nucleotide of an exon (PVS1_Moderate). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There is an RNA assay demonstrating an abnormal out-of-frame transcript for this variant (PS3; PMID: 9537325). Additionally, the variant has also been reported in at least two families meeting HDGC clinical criteria (PS4_Moderate; PMID: 9537325 and internal laboratory data). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Moderate, PM2_Supporting, PS3, PS4_Moderate.

Met criteria codes

• PS3: PMID: 9537325- RT-PCR and sequencing shows activation of a cryptic splice site. Results in inclusion of 7bp from the intron. Will create an early STOP in exon 8. RNA sequencing demonstrated this variant results in a 7-bp insertion (r.1007_1008insTGTCAGG, p.(Glu336Aspfs*16)) in a major transcript, with other minor transcripts showing frameshifts detected (internal data).
• PS4_Moderate: Two families meeting IGCLC criteria, including the original Maori family reported by Guilford et al. (PMID: 9537325) and in a proband with bilateral LBC and FHx of unspecified gastric, breast, and abdominal cancers (internal data).
• PVS1_Moderate: G to non-G variants disrupting the last nucleotide of an exon.
• PM2_Supporting: Based on ExAC, 1000 Genomes, or ESP.

Not Met criteria codes

• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS3: PMID: 9537325- RT-PCR and sequencing shows activation of a cryptic splice site. Results in inclusion of 7bp from the intron. Will create an early STOP in exon 8.
• BS1: Based on ExAC, 1000 Genomes, or ESP.
• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: Splice predictors - all three predict loss of splice site; using PVS1_moderate instead
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP4: PMID: 9537325 1 family with DGC. Family in spreadsheet does not have details on GC being DGC, will not count.
• PP1: One big family, multiple generations affected with DGC. Linkage analysis points to CDH1 gene, haplotype analysis shows it is found in affected, obligate carriers and some unaffected. Variant genotyped in 2 affected and 4 obligate carriers.
• PP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP3: Splice predictors - all three predict loss of splice site; using PVS1_moderate instead
• PM3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BA1: Based on ExAC, 1000 Genomes, or ESP.