16-23607918-G-C

Variant names:

• chr16-23607918-G-C
• rs142132127
• NM_024675.4:c.3296C>G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_024675.4(PALB2):​c.3296C>G​(p.Thr1099Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000353 in 1,614,060 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1099T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:19 B:3
• Conservation: PhyloP100: 3.68

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]

ENSG00000261723 (HGNC:58305):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• BP6: Variant 16-23607918-G-C is Benign according to our data. Variant chr16-23607918-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 142504.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=17}. Variant chr16-23607918-G-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4	c.3296C>G	p.Thr1099Arg	missense_variant	Exon 12 of 13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.3296C>G	p.Thr1099Arg	missense_variant	Exon 12 of 13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152090 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000636 AC: 16 AN: 251484 Hom.: 0 AF XY: 0.0000441 AC XY: 6 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000527

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000356 AC: 52 AN: 1461852 Hom.: 0 Cov.: 32 AF XY: 0.0000385 AC XY: 28 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74414

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:19 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:6

Jan 12, 2022

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Mar 06, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with arginine at codon 1099 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function. A functional study has shown that this variant does not affect the homology-directed DNA repair function of PALB2 protein (PMID: 31636395). This variant has been reported in individuals affected with breast cancer (PMID: 25186627, 26976419, 28779002), bladder and colorectal cancer (PMID: 30883245), and ovarian cancer (PMID: 26315354), and this variant has been detected in a breast cancer case-control meta-analysis in 6/60466 cases and 4/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010286). This variant also has been reported in a suspected atypical Fanconi anemia case in a homozygous carrier from a consanguineous marriage (DOI: 10.3892/br.2024.1756). This variant has been reported in 1 individual age 70 years or older without cancer in the FLOSSIES database (https://whi.color.com/variant/16-23619239-G-C), and it also has been identified in 17/282868 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. -

Aug 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T1099R variant (also known as c.3296C>G), located in coding exon 12 of the PALB2 gene, results from a C to G substitution at nucleotide position 3296. The threonine at codon 1099 is replaced by arginine, an amino acid with similar properties. This alteration has previously been reported in individuals at risk for hereditary breast, ovarian, and pancreatic cancers (Tung N et al. Cancer. 2015 Jan;121(1):25-33; Ramus SJ et al. J. Natl. Cancer Inst. 2015 Aug;27;107(11); Decker B et al. J Med Genet. 2017 11;54:732-741; Abe T et al. J. Clin. Oncol. 2019 05;37(13):1070-1080; Tsaousis GN et al. BMC Cancer. 2019 Jun;19:535). This variant was also reported in 6/60,466 breast cancer cases and in 4/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant has been identified in the homozygous state in an individual with features consistent with Fanconi anemia (Abdulkareem AA et al. Biomed Rep, 2024 Apr;20:67). This alteration was found to be functional in a homology-directed DNA repair (HDR) assay (Wiltshire T et al. Genet. Med. 2020 Mar;22(3):622-632). 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. -

Aug 01, 2018

GeneKor MSA

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 15, 2022

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 02, 2018

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast Uncertain:3 Benign:2

Mar 22, 2016

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 13, 2019

Leiden Open Variation Database

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. -

Feb 21, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 31, 2023

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:4

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 04, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate no damaging effect: homology directed DNA repair activity similar to wild type (PMID: 31636395); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast, ovarian, pancreatic, or colorectal cancer, but also in unaffected controls (PMID: 26315354, 28779002, 25186627, 31428572, 33471991, 30883245, 36627197, 35610400); This variant is associated with the following publications: (PMID: 25186627, 26315354, 26976419, 28779002, 31159747, 31422574, 30883245, 33471991, 31428572, 31636395, 24485656, 19609323, 20871615, 36627197, 35610400, 38476606, 35402282) -

Sep 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PALB2 c.3296C>G; p.Thr1099Arg variant (rs142132127) is reported in the literature in individuals affected with breast or ovarian cancer but also in healthy controls (Breast Cancer Association Consortium 2021, Ramus 2015, Tung 2015). Additionally, this variant has been reported in the homozygous state in an individual with features of Fanconi anemia (Abdulkareem 2024). This variant is found in the general population with an overall allele frequency of 0.006% (17/282,868 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.214). However, functional analyses suggest the variant has homology-directed repair activity similar to wildtype PALB2 (Wiltshire 2020). Due to limited and conflicting information, the clinical significance of this variant is uncertain at this time. References: Abdulkareem AA et al. Whole exome sequencing of a novel homozygous missense variant in PALB2 gene leading to Fanconi anaemia complementation group. Biomed Rep. 2024 Mar 1;20(4):67. PMID: 38476606. Breast Cancer Association Consortium et al. Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. N Engl J Med. 2021 Feb 4;384(5):428-439. PMID: 33471991. Ramus SJ et al. Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer. J Natl Cancer Inst. 2015 Aug 27;107(11):djv214. PMID: 26315354. Tung N et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer. 2015 Jan 1;121(1):25-33. PMID: 25186627. Wiltshire T et al. Functional characterization of 84 PALB2 variants of uncertain significance. Genet Med. 2020 Mar;22(3):622-632. PMID: 31636395. -

Nov 29, 2017

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia complementation group N Pathogenic:1 Uncertain:2

Mar 10, 2020

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 2025

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 21, 2019

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in patients with ovarian cancer [PMID 26315354] -

not specified Uncertain:2 Benign:1

Jul 03, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 10, 2025

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PALB2 c.3296C>G (p.Thr1099Arg) results in a non-conservative amino acid change located in the Partner and localiser of BRCA2, WD40 domain (IPR031920) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.5e-05 in 1624922 control chromosomes, predominantly at a frequency of 0.00012 within the South Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in PALB2 causing Hereditary Breast And Ovarian Cancer Syndrome (3.5e-05 vs 0.00016), allowing no conclusion about variant significance. c.3296C>G has been reported in the literature in a homozygous individual affected with Fanconi anemia, and has also been reported in the heterozygous state as a VUS in individuals affected with breast and/or ovarian cancer, as well as in individuals with colon, gastric, or bladder cancer, without strong evidence for causality (e.g. Ramus_2015, Tung_2015, Tung_2016, Abe_2019, Zhunussova_2019, Gonzalez_2022, Zhang_2023). These data indicate that the variant may be associated with disease. A co-occurrence with a pathogenic variant in another cancer-related gene has been observed (ATM c.901+1G>A, internal data). At least one publication reports experimental evidence evaluating an impact on protein function using a homology directed repair assay and showed no damaging effect of this variant on HDR function versus the WT protein (Wiltshire_2019). The following publications have been ascertained in the context of this evaluation (PMID: 30883245, 35610400, 31422574, 26315354, 25186627, 26976419, 31636395, 31428572, 36627197, 38476606). ClinVar contains an entry for this variant (Variation ID: 142504). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Jun 14, 2017

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 Uncertain:1

Mar 10, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast-ovarian cancer, familial, susceptibility to, 5 Uncertain:1

Apr 22, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.66	D;D
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	2.0	.;M
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Benign	0.21
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	.;D
Vest4		0.87
MutPred		0.33		.;Gain of solvent accessibility (P = 0.008);
MVP		0.72
MPC		0.35
ClinPred		0.57	D
GERP RS		6.1
Varity_R		0.73
gMVP		0.58

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: rs142132127; hg19: chr16-23619239; COSMIC: COSV55162019;