Submissions for variant NM_004329.3(BMPR1A):c.499A>G (p.Met167Val)

gnomAD frequency: 0.00007  dbSNP: rs200951235

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002228598	SCV000218862	likely benign	Juvenile polyposis syndrome	2025-01-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000254949	SCV000321418	uncertain significance	not provided	2024-04-28	criteria provided, single submitter	clinical testing	Observed in individuals with a personal or family history of colorectal, breast, or other cancers (PMID: 27153395, 25186627, 25980754, 28135145); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28135145, 25980754, 25186627, 27153395, 31159747, 31668570, 28119430, 30426508)
Ambry Genetics	RCV000493778	SCV000581485	likely benign	Hereditary cancer-predisposing syndrome	2018-09-20	criteria provided, single submitter	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.
Color Diagnostics, LLC DBA Color Health	RCV000493778	SCV000682897	likely benign	Hereditary cancer-predisposing syndrome	2021-03-16	criteria provided, single submitter	clinical testing
Counsyl	RCV000168197	SCV000786602	uncertain significance	Generalized juvenile polyposis/juvenile polyposis coli	2018-06-05	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000493778	SCV000821914	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001264537	SCV001442741	likely benign	not specified	2020-10-29	criteria provided, single submitter	clinical testing	Variant summary: BMPR1A c.499A>G (p.Met167Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251294 control chromosomes (gnomAD). The observed variant frequency is approximately 30-fold of the estimated maximal expected allele frequency for a pathogenic variant in BMPR1A causing Juvenile Polyposis Syndrome phenotype (2e-06), strongly suggesting that the variant is benign. c.499A>G has been reported in the literature in individuals affected with breast and/or ovarian cancer or colorectal cancer (e.g. Tung_2015, Maxwell_2016, Yurgelun_2017, Schubert_2019). One of the reports classified the variant as Likely Benign based on evidence of non-segregation with disease (breast and/or ovarian cancer) following familial studies (Maxwell_2016). These reports do not provide unequivocal conclusions about association of the variant with Juvenile Polyposis Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance while one ClinVar submitter (evaluation after 2014) cites it as likely benign reporting data of co-occurrence with a mutation in another gene that clearly explains a proband's phenotype (SCV000581485.3). Based on the evidence outlined above, the variant was classified as likely benign.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000168197	SCV001737464	uncertain significance	Generalized juvenile polyposis/juvenile polyposis coli	2021-05-13	criteria provided, single submitter	clinical testing	The BMPR1A c.499A>G (p.Met167Val) missense change has a maximum subpopulation frequency of 0.016% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/10-88659852-A-G?dataset=gnomad_r2_1). Six of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in at least one individual with colorectal cancer (PMID: 28135145) and in individuals with breast and/or ovarian cancer (PMID: 31159747). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4.
Sema4, Sema4	RCV000493778	SCV002528605	likely benign	Hereditary cancer-predisposing syndrome	2020-12-26	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV002228598	SCV004019452	uncertain significance	Juvenile polyposis syndrome	2023-03-02	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000254949	SCV004222530	likely benign	not provided	2022-05-11	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001264537	SCV005090856	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing