Variant: NM_024675.3(PALB2):c.3054G>C (p.Glu1018Asp)

CA294183

126708 (ClinVar)

Gene: PALB2

Condition: hereditary breast cancer

Inheritance Mode: Autosomal dominant inheritance

UUID: b9dcdd59-819e-404b-8621-7ddc360ccb68

Approved on: 2023-04-05

Published on: 2023-04-07

HGVS expressions

NM_024675.3:c.3054G>C
NM_024675.3(PALB2):c.3054G>C (p.Glu1018Asp)
NC_000016.10:g.23621421C>G
CM000678.2:g.23621421C>G
NC_000016.9:g.23632742C>G
CM000678.1:g.23632742C>G
NC_000016.8:g.23540243C>G
NG_007406.1:g.24937G>C
ENST00000261584.9:c.3054G>C
ENST00000261584.8:c.3054G>C
ENST00000568219.5:c.2169G>C
NM_024675.4:c.3054G>C
NM_024675.4(PALB2):c.3054G>C (p.Glu1018Asp)

Benign

• Met criteria codes: BA1 BS2 BP1

• Not Met criteria codes: BS3 BP4

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.3054G>C variant in PALB2 is a missense variant predicted to cause substitution of glutamate by aspartate at amino acid 1018 (p.Glu1018Asp). The filtering allele frequency in gnomAD v2.1.1 is 0.004 in the East Asian population, which is higher than the ClinGen HBOP threshold (>0.001) for BA1, and therefore meets this criterion. This variant has been observed in a homozygous state and phase unknown with numerous other PALB2 variants that are tentatively classified as likely pathogenic or pathogenic by the HBOP VCEP in individuals without Fanconi Anemia (GeneDx, Ambry Genetics, Invitae). This variant is functional in multiple different protein assays (PMID 31757951); 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 benign 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. (BA1, BP2_Moderate, BP1)

Met criteria codes

• BA1: The filtering allele frequency in gnomAD v2.1.1 is 0.004 in the East Asian population, which is higher than the ClinGen HBOP threshold (>.001) for BA1, and therefore meets this criterion (BA1).
• BS2: This variant has been observed in a homozygous state or phase unknown with numerous other PALB2 variants that are tentatively classified as likely pathogenic or pathogenic including c.2108T>G (p.Leu703Ter); c.3350+5G>A; c.3179_3180insAlu; c.3351-1G>C; c.2968G>T (p.Glu990Ter) (GeneDx, Ambry Genetics, Invitae) which are tentatively classified as pathogenic or likely pathogenic by the ClinGen HBOP VCEP in individuals without Fanconi Anemia. The phase of the variants was not determined (BS2_Moderate).
• 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

• BS3: This variant is functional in multiple different protein assays (31757951); however due to a lack of positive missense controls with known clinical impact, protein assays do not meet the requirements for use by the ClinGen HBOP VCEP.
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline