chr16-23614083-T-G

Position:

• chr16-23614083-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 0.841

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 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/exons	MANE	Protein	UniProt
PALB2	NM_024675.4	c.3122A>C	p.Lys1041Thr	missense_variant	11/13	ENST00000261584.9	NP_078951.2

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250404 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135364

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 SAS 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

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: 0.00000362

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000595

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 14, 2022	The p.K1041T variant (also known as c.3122A>C), located in coding exon 11 of the PALB2 gene, results from an A to C substitution at nucleotide position 3122. The lysine at codon 1041 is replaced by threonine, an amino acid with similar properties. This alteration was reported in 1/360 Chinese women with hereditary breast cancer who previously tested negative for BRCA1 and BRCA2 mutations (Cao AY et al. Breast Cancer Res. Treat. 2009 Apr;114:457-62). This alteration has also been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 15, 2022	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 (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 18446436) and in a breast cancer case-control meta-analysis in 1/60463 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -

Familial cancer of breast Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 14, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 20, 2023	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 17, 2016

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	1.7	.;L
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Benign	0.11
Sift	Uncertain	0.020	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.66	.;P
Vest4		0.41
MutPred		0.31		.;Loss of MoRF binding (P = 0.0442);
MVP		0.55
MPC		0.37
ClinPred		0.91	D
GERP RS		1.2
Varity_R		0.19
gMVP		0.41

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: rs781663559; hg19: chr16-23625404;