16-23638106-C-G

Variant names:

• chr16-23638106-C-G
• rs587781986
• NM_024675.4:c.72G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024675.4(PALB2):​c.72G>C​(p.Leu24Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L24W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.389
• Publications: 5 publications found

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]

PALB2 Gene-Disease associations (from GenCC):

• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
• Fanconi anemia complementation group N

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• pancreatic cancer, susceptibility to, 3

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• familial ovarian cancer

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32777554).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4	c.72G>C	p.Leu24Phe	missense_variant	Exon 2 of 13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.72G>C	p.Leu24Phe	missense_variant	Exon 2 of 13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

May 30, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PALB2 c.72G>C (p.Leu24Phe) variant has been reported in the published literature in individuals affected with breast cancer (PMID: 28825143 (2017), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/PALB2)). This variant is also found in a reportedly healthy individual (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/PALB2)). One functional study reports this variant to result in ~50% of wild-type PALB2 activity (PMID: 35853885 (2022)). However, it is inconclusive whether this level of activity is low enough to consider this variant as damaging. This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome Uncertain:1

Apr 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L24F variant (also known as c.72G>C), located in coding exon 2 of the PALB2 gene, results from a G to C substitution at nucleotide position 72. The leucine at codon 24 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been detected in a sporadic and familial Chinese breast cancer patient, respectively. (Zhang K et al. Breast Cancer Res. Treat., 2017 Aug).This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.48	T;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.33	T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.8	M;.
PhyloP100		0.39
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.8	D;.
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.036	D;.
Polyphen		1.0	D;.
Vest4		0.56
MutPred		0.25		Gain of methylation at K25 (P = 0.034);.;
MVP		0.81
MPC		0.36
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.59
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs587781986; hg19: chr16-23649427;