Variant: NM_024675.4(PALB2):c.3049G>A (p.Ala1017Thr)

CA7963442

830187 (ClinVar)

Gene: PALB2

Condition: hereditary breast cancer

Inheritance Mode: Autosomal dominant inheritance

UUID: 41b0eb5f-9d5b-482c-bbdb-29ee7c325e9d

HGVS expressions

NM_024675.4:c.3049G>A
NM_024675.4(PALB2):c.3049G>A (p.Ala1017Thr)
NC_000016.10:g.23621426C>T
CM000678.2:g.23621426C>T
NC_000016.9:g.23632747C>T
CM000678.1:g.23632747C>T
NC_000016.8:g.23540248C>T
NG_007406.1:g.24932G>A
ENST00000261584.9:c.3049G>A
ENST00000261584.8:c.3049G>A
ENST00000568219.5:c.2164G>A
NM_024675.3:c.3049G>A

Uncertain Significance

• Met criteria codes: BP1

• Not Met criteria codes: PM2 BS3

Expert Panel

Hereditary Breast, Ovarian and Pancreatic Cancer VCEP

Criteria Specification Information

Criteria Specification: ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PALB2 Version 1.0.0

Evidence submitted by expert panel

Hereditary Breast, Ovarian and Pancreatic Cancer VCEP

The c.3049G>A (p.Ala1017Thr) variant in PALB2 is a missense variant predicted to cause a substitution of alanine by threonine at amino acid 1017 (p.Ala1017Thr). This variant has a minor allele frequency in gnomAD v2.1.1 of 0.00003 in the South Asian population (PM2_Supporting, BS1, and BA1 are not met). This variant is functional in a protein assay (PMID: 31586400); however due to a lack of positive missense controls with known clinical impact, these protein assays do not meet the requirements for use by the HBOP VCEP. PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP (BP1)

Met criteria codes

• BP1: PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease.

Not Met criteria codes

• PM2: GnomAD AF 0.003% (SAS)
• BS3: This variant is functional in a protein assay (PMID: 31586400); however due to a lack of known positive missense controls with known clinical impact, protein assays do not meet the requirements for use by the HBOP VCEP.

Approved on: 2023-04-05

Published on: 2023-04-07