The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
Criteria Specification: CSpec Registry PDF

Variant: NM_001276761.1:c.802+1G>A

CA397836247

633606 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
UUID: e5597807-7124-425a-b33a-5c6af85c5edc

HGVS expressions

NM_001276761.1:c.802+1G>A
NC_000017.11:g.7673700C>T
CM000679.2:g.7673700C>T
NC_000017.10:g.7577018C>T
CM000679.1:g.7577018C>T
NC_000017.9:g.7517743C>T
NG_017013.2:g.18851G>A
NM_000546.5:c.919+1G>A
NM_001126112.2:c.919+1G>A
NM_001126113.2:c.919+1G>A
NM_001126114.2:c.919+1G>A
NM_001126115.1:c.523+1G>A
NM_001126116.1:c.523+1G>A
NM_001126117.1:c.523+1G>A
NM_001126118.1:c.802+1G>A
NM_001276695.1:c.802+1G>A
NM_001276696.1:c.802+1G>A
NM_001276697.1:c.442+1G>A
NM_001276698.1:c.442+1G>A
NM_001276699.1:c.442+1G>A
NM_001276760.1:c.802+1G>A
NM_001276695.2:c.802+1G>A
NM_001276696.2:c.802+1G>A
NM_001276697.2:c.442+1G>A
NM_001276698.2:c.442+1G>A
NM_001276699.2:c.442+1G>A
NM_001276760.2:c.802+1G>A
NM_001276761.2:c.802+1G>A
ENST00000269305.8:c.919+1G>A
ENST00000359597.8:n.919+1G>A
ENST00000413465.6:n.782+481G>A
ENST00000420246.6:c.919+1G>A
ENST00000445888.6:c.919+1G>A
ENST00000455263.6:c.919+1G>A
ENST00000504290.5:c.523+1G>A
ENST00000504937.5:c.523+1G>A
ENST00000509690.5:c.523+1G>A
ENST00000510385.5:c.523+1G>A
ENST00000610292.4:c.802+1G>A
ENST00000610538.4:c.802+1G>A
ENST00000610623.4:c.442+1G>A
ENST00000615910.4:n.886+1G>A
ENST00000617185.4:c.919+1G>A
ENST00000618944.4:c.442+1G>A
ENST00000619186.4:c.442+1G>A
ENST00000619485.4:c.802+1G>A
ENST00000620739.4:c.802+1G>A
ENST00000622645.4:c.802+1G>A
ENST00000635293.1:c.802+1G>A

Likely Pathogenic

Met criteria codes 3
PVS1_Strong PM6_Supporting PM2_Supporting
Unmet criteria codes 2
PS2 PS4

Expert Panel

Evidence Links 1

Evidence submitted by expert panel
TP53 VCEP
The c.919+1G>A is canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There is a proband with a de novo observation with bilateral, metachronous breast cancer without mention of parental confirmation (PM6_Supporting; PMID: 28509937). In summary, TP53 c.919+1G>A meets criteria to be classified as likely pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PVS1_Strong, PM2_Supporting, PM6_Supporting.
Met criteria codes
PVS1_Strong
Canonical splice variant
PM6_Supporting
This variant was seen in a female with a personal history of bilateral, metachronous breast cancer diagnoses at age 33 and 36. Points = 0.5
PM2_Supporting
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Unmet criteria codes
PS2
Clinical case submitted by EP member: proband w/breast cancer at 26 (not used since case is unpublished and not in ClinVar)
PS4
Variant in several probands with breast cancer but none meet Chompret criteria.

Approved on: 2019-08-28
Published on: 2020-01-24
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