rs374425261

Positions:

• chr16-23636208-G-A
• chr16-23636208-G-C
• chr16-23636208-G-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.338C>T (p.Pro113Leu) variant in PALB2 is a missense variant predicted to cause substitution of proline by leucine at amino acid 113 (p.Pro113Leu). 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. (PM2_Supporting, BP1) LINK:https://erepo.genome.network/evrepo/ui/classification/CA395137757/MONDO:0016419/020

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 B:1
• Conservation: PhyloP100: 0.454

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.338C>T	p.Pro113Leu	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.338C>T	p.Pro113Leu	missense_variant	4/13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 22, 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	Sep 21, 2018	- -

Familial cancer of breast Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen

Apr 05, 2023

The c.338C>T (p.Pro113Leu) variant in PALB2 is a missense variant predicted to cause substitution of proline by leucine at amino acid 113 (p.Pro113Leu). 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. (PM2_Supporting, BP1) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	14
DANN	Benign	0.81
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.95	L
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.012
Sift	Benign	0.26	T
Sift4G	Benign	0.14	T
Polyphen		0.0040	B
Vest4		0.12
MutPred		0.23		Gain of catalytic residue at P113 (P = 0.0451);
MVP		0.40
MPC		0.054
ClinPred		0.070	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.033
gMVP		0.033

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: rs374425261; hg19: chr16-23647529;