16-23614083-T-G

Variant names:

• chr16-23614083-T-G
• rs781663559
• NM_024675.4:c.3122A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024675.4(PALB2):​c.3122A>C​(p.Lys1041Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,454,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1041E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 0.841
• Publications: 6 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

ENSG00000261723 (HGNC:58305):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21413219).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4	c.3122A>C	p.Lys1041Thr	missense_variant	Exon 11 of 13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.3122A>C	p.Lys1041Thr	missense_variant	Exon 11 of 13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250404 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1454620 Hom.: 0 Cov.: 28 AF XY: 0.00000276 AC XY: 2 AN XY: 724152

African (AFR) AF: 0.00 AC: 0 AN: 33308

American (AMR) AF: 0.00 AC: 0 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.00 AC: 0 AN: 85986

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000362 AC: 4 AN: 1105732

Other (OTH) AF: 0.00 AC: 0 AN: 60158

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000595

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Mar 13, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Aug 01, 2018

GeneKor MSA

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 26, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces lysine with threonine at codon 1041 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individuals or families affected with breast or other cancers (PMID: 18446436, 36980780; DOI: 10.30569/adiyamansaglik.1378620) and it also has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 2/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010783). This variant has been identified in 1/250404 chromosomes 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.

Familial cancer of breast Uncertain:2

Nov 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 1041 of the PALB2 protein (p.Lys1041Thr). This variant is present in population databases (rs781663559, gnomAD 0.0009%). This missense change has been observed in individual(s) with pediatric acute myeloid leukemia and a personal and/or family history of breast cancer (PMID: 18446436, 31159747, 31470354). ClinVar contains an entry for this variant (Variation ID: 422560). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PALB2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect PALB2 function (PMID: 31586400). 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.

Dec 20, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:1

Oct 17, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted PALB2 c.3122A>C at the cDNA level, p.Lys1041Thr (K1041T) at the protein level, and results in the change of a Lysine to a Threonine (AAA>ACA). This variant has been observed in at least one individual with either a personal or family history of breast and/or ovarian cancer (Cao 2009). PALB2 Lys1041Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Lysine and Threonine differ in some properties, this is considered a semi-conservative amino acid substitution. PALB2 Lys1041Thr occurs at a position that is not conserved and is located within the WD4 repeat region, a region required for interaction with POLH and POLH DNA synthesis stimulation, as well as a region of interaction with RAD51 and BRCA2 (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether PALB2 Lys1041Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.054	T;T
Eigen	Benign	-0.010
Eigen_PC	Benign	0.0093
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	.;L
PhyloP100		0.84
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Benign	0.0
Sift	Uncertain	0.020	D;D
Sift4G	Uncertain	0.0070	D;D
Vest4		0.41
ClinPred		0.91	D
GERP RS		1.2
Varity_R		0.19
gMVP		0.41
Mutation Taster		=63/37	polymorphism

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

Other links and lift over

dbSNP: rs781663559; hg19: chr16-23625404;