16-23637951-C-T

Position:

chr16-23637951-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001407304.1(PALB2):c.-776G>A variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000391 in 1,613,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

PALB2
NM_001407304.1 5_prime_UTR_premature_start_codon_gain

Scores

Splicing: ADA: 0.1525

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12B:1

Conservation

PhyloP100: 4.37

Variant links:

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 links:

PALB2 (HGNC:):

PALB2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.25478855).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.110G>A	p.Arg37His	missense_variant, splice_region_variant	3/13	ENST00000261584.9	NP_078951.2	Q86YC2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9 linkuse as main transcript	c.110G>A	p.Arg37His	missense_variant, splice_region_variant	3/13	1	NM_024675.4	ENSP00000261584.4		Q86YC2

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152034

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251458

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000376

AC:

AN:

1460938

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

726822

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000432

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000919

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000330

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial cancer of breast

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 20, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 03, 2023	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]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 37 of the PALB2 protein (p.Arg37His). This variant is present in population databases (rs202194596, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer, colorectal cancer, and personal or family history of breast and/or ovarian cancer (PMID: 22241545, 23934836, 23935836, 27978560, 28779002, 36175305). ClinVar contains an entry for this variant (Variation ID: 126590). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PALB2 function (PMID: 28319063, 31586400, 31636395, 31757951, 33139182). 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	Mar 15, 2024	- -

not provided

Uncertain:3

Uncertain significance, no assertion criteria provided	curation	Leiden Open Variation Database	May 13, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Melissa DeRycke. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 05, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal or family history including breast, colorectal, pancreatic, and other cancers (Tischkowitz et al., 2012; Blanco et al., 2013; Decker et al., 2017; Pearlman et al., 2017); This variant is associated with the following publications: (PMID: 27978560, 23935836, 22241545, 28319063, 25428177, 28678401, 28779002, 31757951, 31586400, 31636395, 32209438, 32185139, 33195396, 33169439, 33811135, 33964450, 33139182, 19369211, 20871615) -

Hereditary cancer-predisposing syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 16, 2023	This missense variant replaces arginine with histidine at codon 37 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). Functional studies of this variant have demonstrated moderate to low effects on homologous recombination, BRCA1-interaction, RAD51 foci formation, and PARP inhibitor sensitivity (PMID: 28319063, 31586400, 31636395, 31757951, 33195396, 33811135). This variant has been reported in individuals affected with breast, pancreatic, prostate, colorectal and head and neck cancer in the literature (PMID: 22241545, 23935836, 27978560, 28678401, 28779002, 31214711, 33309985, 33471991, 33811135). This variant also has been reported in two individuals unaffected with breast cancer (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010020). This variant has been identified in 11/282840 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	Ambry Genetics	Sep 05, 2023	The p.R37H variant (also known as c.110G>A), located in coding exon 3 of the PALB2 gene, results from a G to A substitution at nucleotide position 110. The arginine at codon 37 is replaced by histidine, an amino acid with highly similar properties. One study identified this alteration in 1/565 unilateral breast cancer cases and 0/559 bilateral breast cancer cases (Tischkowitz M et al. Hum. Mutat. 2012 Apr;33:674-80). Another study identified this alteration in 1/132 BRCA1/2-negative Spanish breast/ovarian cancer families with at least one case of pancreatic cancer (Blanco A et al. PLoS ONE. 2013 Jul;8:e67538). This variant has also been identified in 1/450 individuals with early onset colorectal cancer and in 1/417 individuals with head and neck squamous cell carcinoma (Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471; Chandrasekharappa SC et al. Cancer. 2017 Oct;123:3943-3954). Functional studies demonstrate that this alteration results in mild reduction in homologous repair activity, but it does not affect PALB2-BRCA1 binding and does not confer sensitivity to platinum therapy, mitomycin C, or olaparib therapy, similar to wild-type (Foo TK et al. Oncogene. 2017 Jul;36:4161-4170). Additional studies have shown that this alteration is functionally normal in a homology-directed DNA repair (HDR) assay (Wiltshire T et al. Genet. Med., 2020 03;22:622-632), but is functionally inconclusive in PARPi sensitivity, cisplatin sensitivity, RAD51 foci formation and BRCA1/2 interaction assays (Boonen RACM et al. Nat Commun, 2019 11;10:5296, Rodrigue A et al. Nucleic Acids Res., 2019 11;47:10662-10677). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is still limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 01, 2022

Variant summary: PALB2 c.110G>A (p.Arg37His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant is also located at the second exonic base from a canonical 3' splice acceptor site. 5/5 computational tools predict no significant impact on normal splicing, which is supported by a functional study (Blanco_2013). The variant allele was found at a frequency of 4e-05 in 251458 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PALB2 causing Hereditary Breast and Ovarian Cancer (4e-05 vs 0.00016), allowing no conclusion about variant significance. c.110G>A has been reported in the literature in sequencing studies of individuals from BRCA families with at-least once case of pancreatic cancer (Blanco_2013); Head and Neck Squamous Cell Carcinoma (HNSCC) (Chandrashekarappa_2017); colorectal cancer (Pearlman_2016); and unilateral breast cancer (Tischkowitz_2012). A systematic review summarizing the earlier reports indicated this variant as not having co-segregated with disease along with a predicted pathogenicity assignment of VUS (Zhan_2018). Therefore, these report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Several publications report conflicting experimental evidence evaluating an impact on the various protein functions examined. While the most pronounced variant effect results in 30%-50% of normal activity in HDR assays (Rodrigue_2019 and Boonen_2019), conflicting results resulting in 50-90% of normal activity in HDR assays have also been reported (Foo_2017 and Wiltshire_2019). The results from the ability of this variant to recruit PALB2 to DNA damage sites report conflicting findings ranging from no effect (Foo_2017, Rodrigue_2019) versus an impaired effect (estimated at 54% of WT, Boonen_2019). Ability to form RAD51C foci also exhibited inter-assay variability ranging from no effect (Foo_2017) to a slightly compromised level estimated at 71% of WT (Rodrigue_2019). Lastly, moderate but statistically significant levels of sensitivity to PARP inhibitors such as Olaparib were reported in two studies (Rodrigue_2019 and Boonen_2019). In summary, an unequivocal correlation of these experimental reports to the in-vivo impact of this variant cannot be established from the findings reviewed. Seven clinical diagnostic laboratories and the LOVD have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as uncertain significance some citing overlapping evidence utilized in the context of this evaluation. Based on the reviewed evidence outlined above, the variant retained its classification as uncertain significance. -

PALB2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 09, 2024

The PALB2 c.110G>A variant is predicted to result in the amino acid substitution p.Arg37His. This variant has been observed in individuals with a history of breast/ovarian and colorectal cancer (Blanco et al. 2013. PubMed ID: 23935836; Pearlman et al. 2017. PubMed ID: 27978560). However, it has also been reported in control cohorts (Supplementary Table S1, Tischkowitz et al. 2012. PubMed ID: 22241545). In vitro functional studies support that this variant does not impact BRCA1 protein interactions but does reduce PALB2 homologous recombination repair activity (Foo et al. 2017. PubMed ID: 28319063). This variant is reported in 0.015% of alleles in individuals of East Asian descent in gnomAD and has conflicting interpretation in ClinVar ranging from uncertain to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/126590/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 28, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.046

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.48

T;T

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.039

MetaRNN

Benign

0.25

T;T

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.7

M;.

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.5

D;.

REVEL

Benign

0.16

Sift

Pathogenic

0.0

D;.

Sift4G

Uncertain

0.0090

D;.

Polyphen

0.97

D;.

Vest4

0.65

MVP

0.78

MPC

0.37

ClinPred

0.95

GERP RS

4.8

Varity_R

0.46

gMVP

0.048

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.15

dbscSNV1_RF

Benign

0.36

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over