chr16-23635675-C-T

Position:

• chr16-23635675-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PM2_Supporting BP1

This summary comes from the ClinGen Evidence Repository: The c.871G>A variant in PALB2 is a missense variant predicted to cause substitution of alanine by threonine at amino acid 291 (p.Ala291Thr). This variant is absent from gnomAD v2.1.1. 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, PM2_Supporting) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10583380/MONDO:0016419/020

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PALB2 ENST00000261584.9 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:4 B:1
• Conservation: PhyloP100: -0.0760

Genes affected

PALB2 (HGNC:26144): (partner and localizer of BRCA2) This gene encodes a protein that may function in tumor suppression. This protein binds to and colocalizes with the breast cancer 2 early onset protein (BRCA2) in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4	c.871G>A	p.Ala291Thr	missense_variant	4/13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.871G>A	p.Ala291Thr	missense_variant	4/13	1	NM_024675.4	ENSP00000261584	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1461776 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727186

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Familial cancer of breast Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 01, 2022	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 291 of the PALB2 protein (p.Ala291Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 241572). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, reviewed by expert panel	curation	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	Apr 05, 2023	The c.871G>A variant in PALB2 is a missense variant predicted to cause substitution of alanine by threonine at amino acid 291 (p.Ala291Thr). This variant is absent from gnomAD v2.1.1. 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, PM2_Supporting) -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 27, 2024	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 04, 2023	This missense variant replaces alanine with threonine at codon 291 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PALB2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	10
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.068
Sift	Benign	0.030	D
Sift4G	Benign	0.14	T
Polyphen		0.33	B
Vest4		0.090
MutPred		0.22		Gain of relative solvent accessibility (P = 0.0479);
MVP		0.43
MPC		0.055
ClinPred		0.23	T
GERP RS		5.1
Varity_R		0.094
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs878855124; hg19: chr16-23646996;